Glycoside derivatives and uses thereof

ABSTRACT

This invention relates to compounds represented by formula (I): 
     
       
         
         
             
             
         
       
     
     wherein the variables are defined as herein above, which are useful for treating diseases and conditions mediated by the sodium D-glucose co-transporter (SGLT), e.g. diabetes. The invention also provides methods of treating such diseases and conditions, and compositions etc. for their treatment.

BACKGROUND OF THE INVENTION

Diabetes mellitus is a metabolic disorder characterized by recurrent orpersistent hyperglycemia (high blood glucose) and other signs, asdistinct from a single disease or condition. Glucose level abnormalitiescan result in serious long-term complications, which includecardiovascular disease, chronic renal failure, retinal damage, nervedamage (of several kinds), microvascular damage and obesity.

Type 1 diabetes, also known as Insulin Dependent Diabetes Mellitus(IDDM), is characterized by loss of the insulin-producing β-cells of theislets of Langerhans of the pancreas leading to a deficiency of insulin.Type-2 diabetes previously known as adult-onset diabetes, maturity-onsetdiabetes, or Non-Insulin Dependent Diabetes Mellitus (NIDDM)—is due to acombination of increased hepatic glucose output, defective insulinsecretion, and insulin resistance or reduced insulin sensitivity(defective responsiveness of tissues to insulin).

Chronic hyperglycemia can also lead to onset or progression of glucosetoxicity characterized by decrease in insulin secretion from β-cell,insulin sensitivity; as a result diabetes mellitus is self-exacerbated[Diabetes Care, 1990, 13, 610].

Chronic elevation of blood glucose level also leads to damage of bloodvessels. In diabetes, the resultant problems are grouped under“microvascular disease” (due to damage of small blood vessels) and“macrovascular disease” (due to damage of the arteries). Examples ofmicrovascular disease include diabetic retinopathy, neuropathy andnephropathy, while examples of macrovascular disease include coronaryartery disease, stroke, peripheral vascular disease, and diabeticmyonecrosis.

Diabetic retinopathy, characterized by the growth of weakened bloodvessels in the retina as well as macular edema (swelling of the macula),can lead to severe vision loss or blindness. Retinal damage (frommicroangiopathy) makes it the most common cause of blindness amongnon-elderly adults in the US. Diabetic neuropathy is characterized bycompromised nerve function in the lower extremities. When combined withdamaged blood vessels, diabetic neuropathy can lead to diabetic foot.Other forms of diabetic neuropathy may present as mononeuritis orautonomic neuropathy. Diabetic nephropathy is characterized by damage tothe kidney, which can lead to chronic renal failure, eventuallyrequiring dialysis. Diabetes mellitus is the most common cause of adultkidney failure worldwide. A high glycemic diet (i.e., a diet thatconsists of meals that give high postprandial blood sugar) is known tobe one of the causative factors contributing to the development ofobesity.

Type 2 diabetes is characterized by insulin resistance and/or inadequateinsulin secretion in response to elevated glucose level. Therapies fortype 2 diabetes are targeted towards increasing insulin sensitivity(such as TZDs), hepatic glucose utilization (such as biguanides),directly modifying insulin levels (such as insulin, insulin analogs, andinsulin secretagogues), increasing incretin hormone action (such asexenatide and sitagliptin), or inhibiting glucose absorption from thediet (such as alpha glucosidase inhibitors) [Nature 2001, 414, 821-827].

Glucose is unable to diffuse across the cell membrane and requirestransport proteins. The transport of glucose into epithelial cells ismediated by a secondary active cotransport system, the sodium-D-glucoseco-transporter (SGLT), driven by a sodium-gradient generated by theNa+/K+-ATPase. Glucose accumulated in the epithelial cell is furthertransported into the blood across the membrane by facilitated diffusionthrough GLUT transporters [Kidney International 2007, 72, S27-S35].

SGLT belongs to the sodium/glucose co-transporter family SLCA5. Twodifferent SGLT isoforms, SGLT1 and SGLT2, have been identified tomediate renal tubular glucose reabsorption in humans [Curr. Opinon inInvestigational Drugs (2007): 8(4), 285-292 and references citedherein]. Both of them are characterized by their different substrateaffinity. Although both of them show 59% homology in their amino acidsequence, they are functionally different. SGLT1 transports glucose aswell as galactose, and is expressed both in the kidney and in theintestine, while SGLT2 is found exclusively in the S1 and S2 segments ofthe renal proximal tubule. As a consequence, glucose filtered in theglomerulus is reabsorbed into the renal proximal tubular epithelialcells by SGLT2, a low-affinity/high-capacity system, residing on thesurface of epithelial cell lining in S1 and S2 tubular segments. Muchsmaller amounts of glucose are recovered by SGLT1, as ahigh-affinity/low-capacity system, on the more distal segment of theproximal tubule. In healthy human, more than 99% of plasma glucose thatis filtered in the kidney glomerulus is reabsorbed, resulting in lessthan 1% of the total filtered glucose being excreted in urine. It isestimated that 90% of total renal glucose absorption is facilitated bySGLT2; remaining 10% is likely mediated by SGLT1 [J. Parenter. EnteralNutr. 2004, 28, 364-371].

SGLT2 was cloned as a candidate sodium glucose co-transporter, and itstissue distribution, substrate specificity, and affinities arereportedly very similar to those of the low-affinity sodium glucoseco-transporter in the renal proximal tubule. A drug with a mode ofaction of SGLT2 inhibition will be a novel and complementary approach toexisting classes of medication for diabetes and its associated diseasesto meet the patient's needs for both blood glucose control, whilepreserving insulin secretion. In addition, SGLT2 inhibitors which leadto loss of excess glucose (and thereby excess calories) may haveadditional potential for the treatment of obesity.

Indeed small molecule SGLT2 inhibitors have been discovered and theanti-diabetic therapeutic potential of such molecules has been reportedin literature [T-1095 (Diabetes, 1999, 48, 1794-1800, Dapagliflozin(Diabetes, 2008, 57, 1723-1729)].

Various O-aryl and O-heteroaryl glycosides have been reported as SGLT-2inhibitors in patent publications such as: WO 01/74834, WO 03/020737,U.S. Ser. No. 04/001,8998, WO 01/68660, WO 01/16147, WO 04/099230, WO05/011592, U.S. Ser. No. 06/029,3252 and WO 05/021566.

Various glucopyranosyl-substituted aromatic and heteroaromatic compoundshave also been reported as SGLT-2 inhibitors in patent publications suchas: WO 01/27128, WO 04/080990, U.S. Ser. No. 06/002,5349, WO 05/085265,WO 05/085237, WO 06/054629 and WO 06/011502.

SGLT1 is predominantly found in the intestine and plays a major role inthe absorption of D-glucose and D-galactose. Therefore, SGLT1 inhibitorshave the potential to act both in the kidney as well as the intestine toreduce calorie intake and hyperglycemia.

WO2004/018491 discloses pyrazole derivatives which are SGLT1 inhibitors.

Glucopyranosyl-substituted aromatic or heteroaromatic compounds where,in general, the sugar moiety has been modified at C4, C5, or C6positions of pyranose have been published (U.S. Ser. No. 06/000,9400,U.S. Ser. No. 06/001,9948, U.S. Ser. No. 06/003,5841, U.S. Ser. No.06/007,4031, U.S. Ser. No. 08/002,7014 and WO 08/016132).

DESCRIPTION OF THE DRAWINGS

FIG. 1 is a differential scanning calorimetry thermogram of a 1:1L-proline co-crystal of(2S,3R,4R,5S,6R)-2-[3-(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triolprepared by method 1.

FIG. 2 is a powder X-ray diffraction pattern for a 1:1 L-prolineco-crystal of(2S,3R,4R,5S,6R)-2-[3-(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triolprepared by method 1.

FIG. 3 is a differential scanning calorimetry thermogram of a 2:1L-proline co-crystal of(2S,3R,4R,5S,6R)-2-[3-(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triolprepared by method 3.

FIG. 4 is a powder X-ray diffraction pattern for a 2:1 L-prolineco-crystal of(2S,3R,4R,5S,6R)-2-[3-(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triolprepared by method 3.

DETAILED DESCRIPTION OF THE INVENTION

This invention relates to compounds useful for treating diseases andconditions mediated by the sodium D-glucose co-transporter (SGLT), e.g.diabetes. The invention also provides methods of treating such diseasesand conditions, and compounds and compositions etc. for their treatment.

The invention provides novel glycoside derivatives, their polymorphs,stereoisomers, pro-drugs, solvates, pharmaceutically acceptable saltsand formulations thereof. The invention also relates to processes forthe preparation of the compounds of the invention.

The compounds of the invention possess sodium-D-glucose co-transporter(SGLT) inhibition effects, which are beneficial for the prophylaxis,management, treatment, control of progression, or adjunct treatment ofdiseases and/or medical conditions where the inhibition of SGLT would bebeneficial, such as diabetes (including Type-I and Type-II), obesity,dyslipidemia, insulin resistance, and other metabolic syndrome, and/ordiabetes-related complications including retinopathy, nephropathy,neuropathy, ischemic heart disease, arteriosclerosis, β-celldysfunction, and as therapeutic and/or prophylactic agents for obesity.

The inventors have found compounds of Formula (I) that are useful forinhibiting SGLT. Accordingly, in a first aspect of the invention, thereis provided a compound represented by Formula (I):

-   -   wherein:    -   Ring A is an C₆₋₁₀aryl which is optionally substituted with one        or more substituents independently selected from the group        consisting of halo, hydroxy, cyano, nitro, C₁₋₆alkyl,        C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy, haloC₁₋₆alkoxy,        C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₄alkyl, haloC₁₋₆alkyl,        C₆₋₁₀aryl, C₆₋₁₀arylC₁₋₄alkyl, —C(O)OR³, —C(O)R³, —C(O)NR⁴R⁵,        —NR⁴R⁵, —CH₂NR⁴R⁵, C₁₋₆alkoxy, C₃₋₇ cycloalkoxy, —S(O)_(p)R³,        —S(O)₂NR⁴R⁵, —OS(O)₂R³, —CH₂C(O)OR³, —CH₂C(O)NR⁴R⁵,        —NR³C(O)NR⁴R⁵, —NR³C(O)OR³, C₆₋₁₀aryloxy, C₂₋₁₀heterocyclyl,        C₂₋₁₀heterocyclylC₁₋₄alkyl, C₁₋₁₀heteroarylC₁₋₄alkyl,        C₁₋₁₀heteroaryl, C₁₋₁₀heteroaryloxy and C₁₋₁₀heterocycloxy;        wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl,        heterocyclyl and heteroaryl groups may be optionally substituted        with one or more substituents selected from the group consisting        of halo, hydroxy, cyano, nitro, C₁₋₆alkyl, —S(O)_(p)R³,        —C(O)OR³, —C(O)R³, —C(O)NR⁴R⁵, —NR⁴R⁵, —CH₂NR⁴R⁵ and C₁₋₆alkoxy;    -   Ring A′ is a 5-, 6- or 7-membered heterocycle, provided that        Ring A′ is not 1,3-dioxole;    -   Y_(a) is a bond or a (C₁-C₆)alkylene which is optionally        substituted with one or more substituents independently selected        from halo, hydroxy, C₁₋₄alkyl, C₁₋₄alkoxy, haloC₁₋₄alkyl;    -   V is hydrogen, halo or —OR^(b);    -   n is 0, 1, 2, or 3;    -   q is 0, 1, 2, or 3;    -   R¹, R^(1a), R^(1b) and R^(1c) are independently selected from        hydrogen, C₁₋₆ alkyl, C₆₋₁₀aryl-C₁₋₄alkyl, —C(O)C₆₋₁₀aryl and        —C(O)C₁₋₆alkyl;    -   R², for each occurrence, is independently selected from the        group consisting of halo, hydroxy, cyano, nitro, C₁₋₆alkyl,        C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₄alkyl, C₆₋₁₀aryl,        C₆₋₁₀arylC₁₋₄alkyl, —C(O)OR³, —C(O)R³, —C(O)NR⁴R⁵, —NR⁴R⁵,        —CH₂NR⁴R⁵, C₁₋₆alkoxy, C₃₋₇ cycloalkoxy, —S(O)_(p)R³,        —S(O)₂NR⁴R⁵, —OS(O)₂R³, —CH₂C(O)OR³, —CH₂C(O)NR⁴R⁵,        —NR³C(O)NR⁴R⁵, —NR³C(O)OR³, C₆₋₁₀aryloxy, C₂₋₁₀heterocyclyl,        C₂₋₁₀heterocyclylC₁₋₄alkyl, C₁₋₁₀heteroarylC₁₋₄alkyl,        C₁₋₁₀heteroaryl, C₁₋₁₀heteroaryloxy and C₁₋₁₀heterocycloxy;        wherein when any portion of R² is an alkyl, cycloalkyl, aryl,        heterocyclyl or heteroaryl, for each occurrence, it may be        optionally substituted with one or more substituents which are        independently selected from halo, hydroxy, C₁₋₄alkyl, and        C₁₋₄alkoxy;    -   R^(2a), for each occurrence, is independently selected from the        group consisting of oxo, halo, hydroxy, cyano, nitro, C₁₋₆alkyl,        C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₄alkyl, C₆₋₁₀aryl,        C₆₋₁₀arylC₁₋₄alkyl, —C(O)OR³, —C(O)R³, —C(O)NR⁴R⁵, —NR⁴R⁵,        —CH₂NR⁴R⁵, C₁₋₆alkoxy, C₃₋₇ cycloalkoxy, —S(O)_(p)R³,        —S(O)₂NR⁴R⁵, —OS(O)₂R³, —CH₂C(O)OR³, —CH₂C(O)NR⁴R⁵,        —NR³C(O)NR⁴R⁵, —NR³C(O)OR³, C₆₋₁₀aryloxy, C₂₋₁₀heterocyclyl,        C₂₋₁₀heterocyclylC₁₋₄alkyl, C₁₋₁₀heteroarylC₁₋₄alkyl,        C₁₋₁₀heteroaryl, C₁₋₁₀heteroaryloxy and C₁₋₁₀heterocycloxy;        wherein when any portion of R^(2a) is an alkyl, cycloalkyl,        aryl, heterocyclyl or heteroaryl, for each occurrence, it may be        optionally substituted with one or more substituents which are        independently selected from halo, hydroxy, cyano, nitro,        C₁₋₆alkyl, —S(O)_(p)R³, —C(O)OR³, —C(O)R³, —C(O)NR⁴R⁵, —NR⁴R⁵,        —CH₂NR⁴R⁵ and C₁₋₆alkoxy; or    -   two R^(2a) on adjacent atoms taken together with the atoms to        which they are attached may form a fused C₃₋₇cycloalkyl, C₆aryl,        3- to 7-membered heterocyclyl, or 5- or 6-membered heteroaryl,        wherein the fused cycloalkyl, aryl, heterocyclyl, and heteroaryl        may be optionally substituted with one or more substituent        independently selected from halo, hydroxy, C₁₋₄alkyl, and        C₁₋₄alkoxy; or    -   two R^(2a) on the same carbon atom taken together may form a        spiro 3- to 7-membered heterocyclyl or a spiro C₃₋₇cycloalkyl        which may be optionally substituted with one or more substituent        independently selected from halo, hydroxy, C₁₋₄alkyl, and        C₁₋₄alkoxy; and    -   R³, for each occurrence, is independently selected from        hydrogen, C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylC₁₋₄alkyl,        C₆₋₁₀aryl, C₁₋₁₀heteroaryl, and C₂₋₁₀heterocyclyl;    -   p is 0, 1 or 2;    -   X is [C(R⁶)(R⁷)]_(t);    -   Y is H, halo, C₁₋₄ alkyl, OR^(1c) or NR⁴R⁵;    -   t is 1, 2, or 3;    -   R⁶ and R⁷, for each occurrence, are independently selected from        hydrogen, C₁₋₆ alkyl, OR^(1e), and NR⁴R⁵;    -   or when t is 1, R⁶ and R⁷ together may form an oxo group,    -   or when R⁶ and R⁷ are on the same carbon they can be taken        together to form a C₃₋₇cycloalkyl or a 3- to 7-membered        heterocycle;    -   R^(1e), for each occurrence, is independently selected from        hydrogen, C₁₋₆ alkyl, C₆₋₁₀aryl-C₁₋₄alkyl, —C(O)C₆₋₁₀aryl and        —C(O)C₁₋₆alkyl;    -   R⁴ and R⁵, for each occurrence, are independently selected from        hydrogen, C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylC₁₋₄alkyl,        C₆₋₁₀arylC₁₋₄alkyl, C₆₋₁₀aryl, C₁₋₁₀heteroaryl,        C₁₋₁₀heteroarylC₁₋₄alkyl, C₂₋₁₀heterocyclyl, and        C₂₋₁₀heterocyclylC₁₋₄alkyl; or    -   R⁴ and R⁵ taken together along with the nitrogen to which they        are bound may form a monocyclic or a bicyclic heteroaryl or        heterocyclyl which may be optionally substituted with one or        more halo or C₁₋₄alkyl; or        a pharmaceutically acceptable salt thereof.

In another aspect of the invention, the compound of Formula (I) is ofFormula (I-a):

-   -   wherein:    -   Ring A is an C₆₋₁₀aryl which is optionally substituted with one        or more substituents independently selected from the group        consisting of halo, hydroxy, cyano, C₁₋₆alkyl, C₂₋₆alkenyl,        C₂₋₆alkynyl, C₁₋₆alkoxy, haloC₁₋₆alkoxy, a 5-membered heteroaryl        and a 6-membered heteroaryl;    -   Ring A′ is a 5- or 6-membered heterocycle, provided that Ring A′        is not 1,3-dioxole;

Y_(a) is a bond or a (C₁-C₆)alkylene which is optionally substitutedwith one or more substituents independently selected from halo,C₁₋₄alkyl, haloC₁₋₄alkyl;

V is hydrogen, halo or —OR^(1b);

-   -   n is 0, 1, 2, or 3;    -   q is 0, 1, 2, or 3;

R¹, R^(1a), R^(1b) and R^(1c) are independently selected from hydrogen,C₁₋₆ alkyl, C₆₋₁₀aryl-C₁₋₄alkyl, —C(O)C₆₋₁₀aryl and —C(O)C₁₋₆alkyl;

R², for each occurrence, is independently selected from the groupconsisting of halo, hydroxy, cyano, nitro, C₁₋₆alkyl, C₃₋₇cycloalkyl,C₃₋₇cycloalkylC₁₋₄alkyl, C₆₋₁₀aryl, C₆₋₁₀arylC₁₋₄alkyl, —C(O)OR³,—C(O)R³, —C(O)NR⁴R⁵, —NR⁴R⁵, —CH₂NR⁴R⁵, C₁₋₆alkoxy, C₃₋₇ cycloalkoxy,—S(O)_(p)R³, —S(O)₂NR⁴R⁵, —OS(O)₂R³, —CH₂C(O)OR³, —CH₂C(O)NR⁴R⁵,—NR³C(O)NR⁴R⁵, —NR³C(O)OR³, C₆₋₁₀aryloxy, C₂₋₁₀heterocyclyl,C₂₋₁₀heterocyclylC₁₋₄alkyl, C₁₋₁₀heteroarylC₁₋₄alkyl, C₁₋₁₀heteroaryl,C₁₋₁₀heteroaryloxy and C₁₋₁₀heterocycloxy; wherein R² may, for eachoccurrence, be optionally substituted with one or more substituentswhich are independently selected from halo, hydroxy, C₁₋₄alkyl, andC₁₋₄alkoxy;

R^(2a), for each occurrence, is independently selected from the groupconsisting of oxo, halo, hydroxy, cyano, nitro, C₁₋₆alkyl,C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₄alkyl, C₆₋₁₀aryl, C₆₋₁₀arylC₁₋₄alkyl,—C(O)OR³, —C(O)R³, —C(O)NR⁴R⁵, —NR⁴R⁵, —CH₂NR⁴R⁵, C₁₋₆alkoxy, C₃₋₇cycloalkoxy, —S(O)_(p)R³, —S(O)₂NR⁴R⁵, —OS(O)₂R³, —CH₂C(O)OR³,—CH₂C(O)NR⁴R⁵, —NR³C(O)NR⁴R⁵, —NR³C(O)OR³, C₆₋₁₀aryloxy,C₂₋₁₀heterocyclyl, C₂₋₁₀heterocyclylC₁₋₄alkyl, C₁₋₁₀heteroarylC₁₋₄alkyl,C₁₋₁₀heteroaryl, C₁₋₁₀heteroaryloxy and C₁₋₁₀heterocycloxy; whereinR^(2a) may, for each occurrence, be optionally substituted with one ormore substituents which are independently selected from halo, hydroxy,C₁₋₄alkyl, and C₁₋₄alkoxy; or

-   -   two R^(2a) on adjacent atoms taken together with the atoms to        which they are attached may form a fused C₃₋₇cycloalkyl, C₆aryl,        3- to 7-membered heterocyclyl, or 5- or 6-membered heteroaryl,        wherein the fused cycloalkyl, aryl, heterocyclyl, and heteroaryl        may be optionally substituted with one or more substituent        independently selected from halo, hydroxy, C₁₋₄alkyl, and        C₁₋₄alkoxy; or    -   two R^(2a) on the same carbon atom taken together may form a        spiro 3- to 7-membered heterocyclyl or a spiro C₃₋₇cycloalkyl        which may be optionally substituted with one or more substituent        independently selected from halo, hydroxy, C₁₋₄alkyl, and        C₁₋₄alkoxy; and    -   R³, for each occurrence, is independently selected from        hydrogen, C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylC₁₋₄alkyl,        C₆₋₁₀aryl, C₁₋₁₀heteroaryl, and C₂₋₁₀heterocyclyl;    -   p is 0, 1 or 2;    -   X is [C(R⁶)(R⁷)]_(t);    -   Y is H, halo, C₁₋₄ alkyl, OR^(1c) or NR⁴R⁵;    -   t is 1, 2, or 3;    -   R⁶ and R⁷, for each occurrence, are independently selected from        hydrogen, C₁₋₆ alkyl, OR^(1e), and NR⁴R⁵;    -   or when t is 1, R⁶ and R⁷ together may form an oxo group,    -   or when R⁶ and R⁷ are on the same carbon they can be taken        together to form a C₃₋₇cycloalkyl or a 3- to 7-membered        heterocycle;    -   R^(1e), for each occurrence, is independently selected from        hydrogen, C₁₋₆ alkyl, C₆₋₁₀aryl-C₁₋₄alkyl, —C(O)C₆₋₁₀aryl and        —C(O)C₁₋₆alkyl;    -   R⁴ and R⁵, for each occurrence, are independently selected from        hydrogen, C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylC₁₋₄alkyl,        C₆₋₁₀arylC₁₋₄alkyl, C₆₋₁₀aryl, C₁₋₁₀heteroaryl,        C₁₋₁₀heteroarylC₁₋₄alkyl, C₂₋₁₀heterocyclyl, and        C₂₋₁₀heterocyclylC₁₋₄alkyl; or    -   R⁴ and R⁵ taken together along with the nitrogen to which they        are bound may form a monocyclic or a bicyclic heteroaryl or        heterocyclyl which may be optionally substituted with one or        more halo or C₁₋₄alkyl; or        a pharmaceutically acceptable salt thereof.

In another aspect of the invention, the compound of Formula (I) is ofFormula (I-i):

-   -   wherein:    -   Ring A is a C₆₋₁₀aryl which is optionally substituted with one        or more substituents independently selected from the group        consisting of halo, hydroxy, C₁₋₃alkyl, C₁₋₃alkoxy,        haloC₁₋₃alkoxy and 5-membered heteroaryl;    -   Ring A′ is a 5- or 6-membered heterocycle containing at least        one O or N heteroatom, provided that Ring A′ is not 1,3-dioxole;

Y_(a) is a bond or a C₁₋₃alkylene which is optionally substituted withone or more substituents independently selected from halo, C₁₋₄alkyl,and haloC₁₋₄alkyl;

-   -   V is hydrogen, halo or —OR^(b);    -   n is 0, 1 or 2;    -   q is 0, 1, 2, or 3;    -   R¹, R^(1a), R^(1b) and R^(1c) are independently selected from        hydrogen, C₁₋₆ alkyl, C₆₋₁₀aryl-C₁₋₄alkyl, —C(O)C₆₋₁₀aryl and        —C(O)C₁₋₆alkyl;

R², for each occurrence, is independently selected from the groupconsisting of halo, hydroxy, cyano, nitro, C₁₋₆alkyl, C₃₋₇cycloalkyl,C₆₋₁₀aryl, C₆₋₁₀arylC₁₋₄alkyl, —C(O)OR³, —C(O)R³, —C(O)NR⁴R⁵, —NR⁴R⁵,—CH₂NR⁴R⁵, C₁₋₆alkoxy, C₃₋₇ cycloalkoxy, —CH₂C(O)OR³, —CH₂C(O)NR⁴R⁵,—NR³C(O)NR⁴R⁵, —NR³C(O)OR³, C₆₋₁₀aryloxy, C₂₋₁₀heterocyclyl,C₁₋₁₀heteroaryl, C₁₋₁₀heteroaryloxy and C₁₋₁₀heterocycloxy; wherein R²may, for each occurrence, be optionally substituted with one or moresubstituents which are independently selected from halo, hydroxy,C₁₋₄alkyl, and C₁₋₄alkoxy;

-   -   R^(2a), for each occurrence, is independently selected from the        group consisting of oxo, hydroxy, C₁₋₆alkyl,        C₃₋₇cycloalkylC₁₋₄alkyl, C₆₋₁₀arylC₁₋₄alkyl, —C(O)OR³, —C(O)R³,        —C(O)NR⁴R⁵ and CH₂C(O)OR³; wherein R^(2a) may, for each        occurrence, be optionally substituted with one or more        substituents which are independently selected from halo,        hydroxy, C₁₋₄alkyl, and C₁₋₄alkoxy; or    -   two R^(2a) on adjacent atoms taken together with the atoms to        which they are attached may form a fused C₃₋₇cycloalkyl, C₆aryl,        3- to 7-membered heterocyclyl, or 5-membered heteroaryl, wherein        the fused cycloalkyl, aryl, heterocyclyl, and heteroaryl may be        optionally substituted with one or more substituent        independently selected from halo, hydroxy, C₁₋₄alkyl, and        C₁₋₄alkoxy; or    -   two R^(2a) on the same carbon atom taken together may form a        spiro 3- to 7-membered heterocyclyl or a spiro C₃₋₇cycloalkyl        which may be optionally substituted with one or more substituent        independently selected from halo, hydroxy, C₁₋₄alkyl, and        C₁₋₄alkoxy; and    -   R³, for each occurrence, is independently selected from        hydrogen, C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylC₁₋₄alkyl,        C₆₋₁₀aryl, C₁₋₁₀heteroaryl, and C₂₋₁₀heterocyclyl;    -   X is [C(R⁶)(R⁷)]_(t);    -   Y is H, halo, C₁₋₄ alkyl, OR^(1c) or NR⁴R⁵;    -   t is 1,2, or 3;    -   R⁶ and R⁷, for each occurrence, are independently selected from        hydrogen, C₁₋₆ alkyl, OR^(1e), and NR⁴R⁵;    -   or when t is 1, R⁶ and R⁷ together may form an oxo group,    -   or when R⁶ and R⁷ are on the same carbon they can be taken        together to form a C₃₋₇cycloalkyl or a 3- to 7-membered        heterocycle;    -   R^(1e), for each occurrence, is independently selected from        hydrogen, C₁₋₆ alkyl, C₆₋₁₀aryl-C₁₋₄alkyl, —C(O)C₆₋₁₀aryl and        —C(O)C₁₋₆alkyl;    -   R⁴ and R⁵, for each occurrence, are independently selected from        hydrogen, C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylC₁₋₄alkyl,        C₆₋₁₀arylC₁₋₄alkyl, C₆₋₁₀aryl, C₁₋₁₀heteroaryl,        C₁₋₁₀heteroarylC₁₋₄alkyl, C₂₋₁₀heterocyclyl, and        C₂₋₁₀heterocyclylC₁₋₄alkyl; or    -   R⁴ and R⁵ taken together along with the nitrogen to which they        are bound may form a monocyclic or a bicyclic heteroaryl or        heterocyclyl which may be optionally substituted with one or        more halo or C₁₋₄alkyl; or        a pharmaceutically acceptable salt thereof.

In another aspect of the invention, the compound of Formula (I) is ofFormula (I-ia):

-   -   wherein:    -   Ring A is an C₆₋₁₀aryl which is optionally substituted with one        or more substituents independently selected from the group        consisting of halo, hydroxy, cyano, nitro, C₁₋₆alkyl,        C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy, haloC₁₋₆alkoxy,        C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₄alkyl, haloC₁₋₆alkyl,        C₆₋₁₀aryl, C₆₋₁₀arylC₁₋₄alkyl, —C(O)OR³, —C(O)R³, —C(O)NR⁴R⁵,        —NR⁴R⁵, —CH₂NR⁴R⁵, C₁₋₆alkoxy, C₃₋₇ cycloalkoxy, —S(O)_(p)R³,        —S(O)₂NR⁴R⁵, —OS(O)₂R³, —CH₂C(O)OR³, —CH₂C(O)NR⁴R⁵,        —NR³C(O)NR⁴R⁵, —NR³C(O)OR³, C₆₋₁₀aryloxy, C₂₋₁₀heterocyclyl,        C₂₋₁₀heterocyclylC₁₋₄alkyl, C₁₋₁₀heteroarylC₁₋₄alkyl,        C₁₋₁₀heteroaryl, C₁₋₁₀heteroaryloxy and C₁₋₁₀heterocycloxy;        wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl,        heterocyclyl and heteroaryl groups may be optionally substituted        with one or more substituents selected from the group consisting        of halo, hydroxy, cyano, nitro, C₁₋₆alkyl, —S(O)_(p)R³,        —C(O)OR³, —C(O)R³, —C(O)NR⁴R⁵, —NR⁴R⁵, —CH₂NR⁴R⁵ and C₁₋₆alkoxy;    -   Ring A′ is a 5- or 6-membered heterocycle containing at least        one O or N heteroatom, provided that Ring A′ is not 1,3-dioxole;    -   Y_(a) is a bond or a C₁₋₃alkylene which is optionally        substituted with one or more substituents independently selected        from halo, C₁₋₄alkyl, haloC₁₋₄alkyl;    -   V is hydrogen, halo or —OR^(1b);    -   n is 0, 1 or 2;    -   q is 0, 1, 2, or 3;    -   p is 0, 1 or 2;    -   R¹, R^(1a), R^(1b) and R^(1c) are independently selected from        hydrogen, C₁₋₆ alkyl, C₆₋₁₀aryl-C₁₋₄alkyl, —C(O)C₆₋₁₀aryl and        —C(O)C₁₋₆alkyl;

R², for each occurrence, is independently selected from the groupconsisting of halo, hydroxy, cyano, nitro, C₁₋₆alkyl, C₃₋₇cycloalkyl,C₆₋₁₀aryl, C₆₋₁₀arylC₁₋₄alkyl, —C(O)OR³, —C(O)R³, —C(O)NR⁴R⁵, —NR⁴R⁵,—CH₂NR⁴R⁵, C₁₋₆alkoxy, C₃₋₇ cycloalkoxy, —CH₂C(O)OR³, —CH₂C(O)NR⁴R⁵,—NR³C(O)NR⁴R⁵, —NR³C(O)OR³, C₆₋₁₀aryloxy, C₂₋₁₀heterocyclyl,C₁₋₁₀heteroaryl, C₁₋₁₀heteroaryloxy and C₁₋₁₀heterocycloxy; wherein R²may, for each occurrence, be optionally substituted with one or moresubstituents which are independently selected from halo, hydroxy,C₁₋₄alkyl, and C₁₋₄alkoxy;

R^(2a), for each occurrence, is independently selected from the groupconsisting of oxo, halo, hydroxy, cyano, nitro, C₁₋₆alkyl,C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₄alkyl, C₆₋₁₀aryl, C₆₋₁₀arylC₁₋₄alkyl,—C(O)OR³, —C(O)R³, —C(O)NR⁴R⁵, —NR⁴R⁵, —CH₂NR⁴R⁵, C₁₋₆alkoxy, C₃₋₇cycloalkoxy, —S(O)_(p)R³, —S(O)₂NR⁴R⁵, —OS(O)₂R³, —CH₂C(O)OR³,—CH₂C(O)NR⁴R⁵, —NR³C(O)NR⁴R⁵, —NR³C(O)OR³, C₆₋₁₀aryloxy,C₂₋₁₀heterocyclyl, C₂₋₁₀heterocyclylC₁₋₄alkyl, C₁₋₁₀heteroarylC₁₋₄alkyl,C₁₋₁₀heteroaryl, C₁₋₁₀heteroaryloxy and C₁₋₁₀heterocycloxy; whereinR^(2a) may, for each occurrence, be optionally substituted with one ormore substituents which are independently selected from halo, hydroxy,C₁₋₄alkyl, and C₁₋₄alkoxy; or

-   -   two R^(2a) on adjacent atoms taken together with the atoms to        which they are attached may form a fused C₃₋₇cycloalkyl, C₆aryl,        3- to 7-membered heterocyclyl, or 5-membered heteroaryl, wherein        the fused cycloalkyl, aryl, heterocyclyl, and heteroaryl may be        optionally substituted with one or more substituent        independently selected from halo, hydroxy, C₁₋₄alkyl, and        C₁₋₄alkoxy; or    -   two R^(2a) on the same carbon atom taken together may form a        spiro 3- to 7-membered heterocyclyl or a spiro C₃₋₇cycloalkyl        which may be optionally substituted with one or more substituent        independently selected from halo, hydroxy, C₁₋₄alkyl, and        C₁₋₄alkoxy; and    -   R³, for each occurrence, is independently selected from        hydrogen, C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylC₁₋₄alkyl,        C₆₋₁₀aryl, C₁₋₁₀heteroaryl, and C₂₋₁₀heterocyclyl;    -   X is [C(R⁶)(R⁷)]_(t);    -   Y is H, halo, C₁₋₄ alkyl, OR^(1c) or NR⁴R⁵;    -   t is 1,2, or 3;    -   R⁶ and R⁷, for each occurrence, are independently selected from        hydrogen, C₁₋₆ alkyl, OR^(1e), and NR⁴R⁵;    -   or when t is 1, R⁶ and R⁷ together may form an oxo group,    -   or when R⁶ and R⁷ are on the same carbon they can be taken        together to form a C₃₋₇cycloalkyl or a 3- to 7-membered        heterocycle;

R^(1e), for each occurrence, is independently selected from hydrogen,C₁₋₆ alkyl, C₆₋₁₀aryl-C₁₋₄alkyl, —C(O)C₆₋₁₀aryl and —C(O)C₁₋₆alkyl;

-   -   R⁴ and R⁵, for each occurrence, are independently selected from        hydrogen, C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylC₁₋₄alkyl,        C₆₋₁₀arylC₁₋₄alkyl, C₆₋₁₀aryl, C₁₋₁₀heteroaryl,        C₁₋₁₀heteroarylC₁₋₄alkyl, C₂₋₁₀heterocyclyl, and        C₂₋₁₀heterocyclylC₁₋₄alkyl; or    -   R⁴ and R⁵ taken together along with the nitrogen to which they        are bound may form a monocyclic or a bicyclic heteroaryl or        heterocyclyl which may be optionally substituted with one or        more halo or C₁₋₄alkyl; or        a pharmaceutically acceptable salt thereof.

In another aspect of the invention, the compound of Formula (I) is ofFormula (I-ii):

-   -   wherein:    -   Ring A is a C₆₋₁₀aryl which is optionally substituted with one        or more substituents independently selected from the group        consisting of halo, hydroxy, C₁₋₃alkyl, C₁₋₃alkoxy,        haloC₁₋₃alkoxy and 5-membered heteroaryl;    -   Ring A′ is a 5- or 6-membered heterocycle containing at least        one O or N heteroatom, provided that Ring A′ is not 1,3-dioxole;    -   Y_(a) is a bond or a C₁₋₃alkylene which is optionally        substituted with one or more substituents independently selected        from halo, C₁₋₄alkyl, haloC₁₋₄alkyl;    -   V is OH;    -   n is 0, 1 or 2;    -   q is 0, 1, 2, or 3;    -   R¹ and R^(1a) are each hydrogen;    -   R², for each occurrence, is independently selected from the        group consisting of halo, hydroxy, cyano, nitro, C₁₋₆alkyl,        C₃₋₇cycloalkyl, C₆₋₁₀aryl, C₆₋₁₀arylC₁₋₄alkyl, —C(O)OR³,        —C(O)R³, —C(O)NR⁴R⁵, —NR⁴R⁵, —CH₂NR⁴R⁵, C₁₋₆alkoxy, C₃₋₇        cycloalkoxy, —CH₂C(O)OR³, —CH₂C(O)NR⁴R⁵, —NR³C(O)NR⁴R⁵,        —NR³C(O)OR³, C₆₋₁₀aryloxy, C₂₋₁₀heterocyclyl, C₁₋₁₀heteroaryl,        C₁₋₁₀heteroaryloxy and C₁₋₁₀heterocycloxy; wherein R² may, for        each occurrence, be optionally substituted with one or more        substituents which are independently selected from halo,        hydroxy, C₁₋₄alkyl, and C₁₋₄alkoxy;    -   R^(2a), for each occurrence, is independently selected from the        group consisting of oxo, hydroxy, C₁₋₆alkyl,        C₃₋₇cycloalkylC₁₋₄alkyl, C₆₋₁₀arylC₁₋₄alkyl, —C(O)OR³, —C(O)R³,        —C(O)NR⁴R⁵ and CH₂C(O)OR³; wherein R^(2a) may, for each        occurrence, be optionally substituted with one or more        substituents which are independently selected from halo,        hydroxy, C₁₋₄alkyl, and C₁₋₄alkoxy; or    -   two R^(2a) on adjacent atoms taken together with the atoms to        which they are attached may form a fused C₃₋₇cycloalkyl, C₆aryl,        3- to 7-membered heterocyclyl, or 5-membered heteroaryl, wherein        the fused cycloalkyl, aryl, heterocyclyl, and heteroaryl may be        optionally substituted with one or more substituent        independently selected from halo, hydroxy, C₁₋₄alkyl, and        C₁₋₄alkoxy; or    -   two R^(2a) on the same carbon atom taken together may form a        spiro 3- to 7-membered heterocyclyl or a spiro C₃₋₇cycloalkyl        which may be optionally substituted with one or more substituent        independently selected from halo, hydroxy, C₁₋₄alkyl, and        C₁₋₄alkoxy; and    -   R³, for each occurrence, is independently selected from        hydrogen, C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylC₁₋₄alkyl,        C₆₋₁₀aryl, C₁₋₁₀heteroaryl, and C₂₋₁₀heterocyclyl;    -   X is [C(R⁶)(R⁷)]_(t);    -   Y is H or OH;    -   t is 1;    -   R⁶ and R⁷, for each occurrence, are independently selected from        hydrogen and C₁₋₃ alkyl;    -   or when t is 1, R⁶ and R⁷ together may form an oxo group;    -   R⁴ and R⁵, for each occurrence, are independently selected from        hydrogen, C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylC₁₋₄alkyl,        C₆₋₁₀arylC₁₋₄alkyl, C₆₋₁₀aryl, C₁₋₁₀heteroaryl,        C₁₋₁₀heteroarylC₁₋₄alkyl, C₂₋₁₀heterocyclyl, and        C₂₋₁₀heterocyclylC₁₋₄alkyl; or    -   R⁴ and R⁵ taken together along with the nitrogen to which they        are bound may form a monocyclic or a bicyclic heteroaryl or        heterocyclyl which may be optionally substituted with one or        more halo or C₁₋₄alkyl; or        a pharmaceutically acceptable salt thereof.

In another aspect of the invention, the compound of Formula (I) is ofFormula (I-iia):

-   -   wherein:    -   Ring A is an C₆₋₁₀aryl which is optionally substituted with one        or more substituents independently selected from the group        consisting of halo, hydroxy, cyano, nitro, C₁₋₆alkyl,        C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy, haloC₁₋₆alkoxy,        C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₄alkyl, haloC₁₋₆alkyl,        C₆₋₁₀aryl, C₆₋₁₀arylC₁₋₄alkyl, —C(O)OR³, —C(O)R³, —C(O)NR⁴R⁵,        —NR⁴R⁵, —CH₂NR⁴R⁵, C₁₋₆alkoxy, C₃₋₇ cycloalkoxy, —S(O)_(p)R³,        —S(O)₂NR⁴R⁵, —OS(O)₂R³, —CH₂C(O)OR³, —CH₂C(O)NR⁴R⁵,        —NR³C(O)NR⁴R⁵, —NR³C(O)OR³, C₆₋₁₀aryloxy, C₂₋₁₀heterocyclyl,        C₂₋₁₀heterocyclylC₁₋₄alkyl, C₁₋₁₀heteroarylC₁₋₄alkyl,        C₁₋₁₀heteroaryl, C₁₋₁₀heteroaryloxy and C₁₋₁₀heterocycloxy;        wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl,        heterocyclyl and heteroaryl groups may be optionally substituted        with one or more substituents selected from the group consisting        of halo, hydroxy, cyano, nitro, C₁₋₆alkyl, —S(O)_(p)R³,        —C(O)OR³, —C(O)R³, —C(O)NR⁴R⁵, —NR⁴R⁵, —CH₂NR⁴R⁵ and C₁₋₆alkoxy;    -   Ring A′ is a 5- or 6-membered heterocycle containing at least        one O or N heteroatom, provided that Ring A′ is not 1,3-dioxole;    -   Y_(a) is a bond or a C₁₋₃alkylene which is optionally        substituted with one or more substituents independently selected        from halo, C₁₋₄alkyl, haloC₁₋₄alkyl;    -   V is OH;    -   n is 0, 1 or 2;    -   q is 0, 1, 2, or 3;    -   R¹ and R^(1a) are each hydrogen;    -   R², for each occurrence, is independently selected from the        group consisting of halo, hydroxy, cyano, nitro, C₁₋₆alkyl,        C₃₋₇cycloalkyl, C₆₋₁₀aryl, C₆₋₁₀arylC₁₋₄alkyl, —C(O)OR³,        —C(O)R³, —C(O)NR⁴R⁵, —NR⁴R⁵, —CH₂NR⁴R⁵, C₁₋₆alkoxy, C₃₋₇        cycloalkoxy, —CH₂C(O)OR³, —CH₂C(O)NR⁴R⁵, —NR³C(O)NR⁴R⁵,        —NR³C(O)OR³, C₆₋₁₀aryloxy, C₂₋₁₀heterocyclyl, C₁₋₁₀heteroaryl,        C₁₋₁₀heteroaryloxy and C₁₋₁₀heterocycloxy; wherein R² may, for        each occurrence, be optionally substituted with one or more        substituents which are independently selected from halo,        hydroxy, C₁₋₄alkyl, and C₁₋₄alkoxy;    -   R^(2a), for each occurrence, is independently selected from the        group consisting of oxo, halo, hydroxy, cyano, nitro, C₁₋₆alkyl,        C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₄alkyl, C₆₋₁₀aryl,        C₆₋₁₀arylC₁₋₄alkyl, —C(O)OR³, —C(O)R³, —C(O)NR⁴R⁵, —NR⁴R⁵,        —CH₂NR⁴R⁵, C₁₋₆alkoxy, C₃₋₇ cycloalkoxy, —S(O)_(p)R³,        —S(O)₂NR⁴R⁵, —OS(O)₂R³, —CH₂C(O)OR³, —CH₂C(O)NR⁴R⁵,        —NR³C(O)NR⁴R⁵, —NR³C(O)OR³, C₆₋₁₀aryloxy, C₂₋₁₀heterocyclyl,        C₂₋₁₀heterocyclylC₁₋₄alkyl, C₁₋₁₀heteroarylC₁₋₄alkyl,        C₁₋₁₀heteroaryl, C₁₋₁₀heteroaryloxy and C₁₋₁₀heterocycloxy;        wherein R^(2a) may, for each occurrence, be optionally        substituted with one or more substituents which are        independently selected from halo, hydroxy, C₁₋₄alkyl, and        C₁₋₄alkoxy; or    -   two R^(2a) on adjacent atoms taken together with the atoms to        which they are attached may form a fused C₃₋₇cycloalkyl, C₆aryl,        3- to 7-membered heterocyclyl, or 5-membered heteroaryl, wherein        the fused cycloalkyl, aryl, heterocyclyl, and heteroaryl may be        optionally substituted with one or more substituent        independently selected from halo, hydroxy, C₁₋₄alkyl, and        C₁₋₄alkoxy; or    -   two R^(2a) on the same carbon atom taken together may form a        spiro 3- to 7-membered heterocyclyl or a spiro C₃₋₇cycloalkyl        which may be optionally substituted with one or more substituent        independently selected from halo, hydroxy, C₁₋₄alkyl, and        C₁₋₄alkoxy; and    -   R³, for each occurrence, is independently selected from        hydrogen, C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylC₁₋₄alkyl,        C₆₋₁₀aryl, C₁₋₁₀heteroaryl, and C₂₋₁₀heterocyclyl;    -   p is 0, 1 or 2;    -   X is [C(R⁶)(R⁷)]_(t);    -   Y is H or OH;    -   t is 1;    -   R⁶ and R⁷, for each occurrence, are independently selected from        hydrogen and C₁₋₃ alkyl;    -   or when t is 1, R⁶ and R⁷ together may form an oxo group;    -   R⁴ and R⁵, for each occurrence, are independently selected from        hydrogen, C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylC₁₋₄alkyl,        C₆₋₁₀arylC₁₋₄alkyl, C₆₋₁₀aryl, C₁₋₁₀heteroaryl,        C₁₋₁₀heteroarylC₁₋₄alkyl, C₂₋₁₀heterocyclyl, and        C₂₋₁₀heterocyclylC₁₋₄alkyl; or    -   R⁴ and R⁵ taken together along with the nitrogen to which they        are bound may form a monocyclic or a bicyclic heteroaryl or        heterocyclyl which may be optionally substituted with one or        more halo or C₁₋₄alkyl; or        a pharmaceutically acceptable salt thereof.

In another aspect of the invention, the compound of Formula (I) is ofFormula (I-iii):

-   -   wherein:    -   Ring A is a phenyl ring which is optionally substituted with one        or more substituents independently selected from the group        consisting of chloro, fluoro, hydroxy, methyl, methoxy, ethoxy,        trifluoromethoxy and N-pyrazolyl;    -   the structure represented by the following formula:

is selected from the group consisting of:

wherein the hydrogen on each nitrogen may be optionally replaced withR^(2a);

-   -   Y_(a) is CH₂;    -   V is OH;    -   n is 0 or 1;    -   q is 0 or 1;    -   R¹ and R^(1a) are each hydrogen;    -   R² is halo; wherein R² may, for each occurrence, be optionally        substituted with one or more substituents which are        independently selected from halo, hydroxy, C₁₋₄alkyl, and        C₁₋₄alkoxy;

R^(2a), for each occurrence, is independently selected from the groupconsisting of hydroxy, C₁₋₆alkyl, C₃₋₇cycloalkylC₁₋₄alkyl; whereinR^(2a) may, for each occurrence, be optionally substituted with one ormore substituents which are independently selected from halo, hydroxy,C₁₋₄alkyl, and C₁₋₄alkoxy; or

-   -   two R^(2a) on the same carbon atom taken together may form a        spiro C₃₋₇cycloalkyl which may be optionally substituted with        one or more substituent independently selected from halo,        hydroxy, C₁₋₄alkyl, and C₁₋₄alkoxy;    -   X is CH₂;    -   Y is OH; or        a pharmaceutically acceptable salt thereof.

In another aspect of the invention, the compound of Formula (I) is ofFormula (I-iiia):

-   -   wherein:    -   Ring A is a phenyl ring which is optionally substituted with one        or more substituents independently selected from the group        consisting of chloro, fluoro, hydroxy, cyano, methyl, ethyl,        isopropyl, ethynyl, methoxy, ethoxy, trifluoromethoxy, amino,        dimethylamino, methylsulfanyl, methylsulfonyl, carbamoyl,        cyclopropyl, cyclobutyl, phenyl, toulyl, phenoxy, oxazolyloxy,        and N-pyrazolyl; the structure represented by the following        formula:

-   -   is selected from the group consisting of:

wherein the hydrogen on each nitrogen may be optionally replaced withR^(2a); R^(a), for each occurrence, is independently selected from halo,hydroxy, cyano, nitro, C₁₋₆alkyl, —S(O)_(p)R³, —C(O)OR³, —C(O)R³,—C(O)NR⁴R⁵, —NR⁴R⁵, —CH₂NR⁴R⁵ and C₁₋₆alkoxy; and m is 0 or an integerfrom 1-4;

-   -   Y_(a) is CH₂;    -   V is OH;    -   n is 0 or 1;    -   q is 0 or 1;    -   R¹ and R^(1a) are each hydrogen;    -   R² is halo; wherein R² may, for each occurrence, be optionally        substituted with one or more substituents which are        independently selected from halo, hydroxy, C₁₋₄alkyl, and        C₁₋₄alkoxy;    -   R^(2a), for each occurrence, is independently selected from the        group consisting of oxo, halo, hydroxy, cyano, nitro, C₁₋₆alkyl,        C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₄alkyl, C₆₋₁₀aryl,        C₆₋₁₀arylC₁₋₄alkyl, —C(O)OR³, —C(O)R³, —C(O)NR⁴R⁵, —NR⁴R⁵,        —CH₂NR⁴R⁵, C₁₋₆alkoxy, C₃₋₇ cycloalkoxy, —S(O)_(p)R³,        —S(O)₂NR⁴R⁵, —OS(O)₂R³, —CH₂C(O)OR³, —CH₂C(O)NR⁴R⁵,        —NR³C(O)NR⁴R⁵, —NR³C(O)OR³, C₆₋₁₀aryloxy, C₂₋₁₀heterocyclyl,        C₂₋₁₀heterocyclylC₁₋₄alkyl, C₁₋₁₀heteroarylC₁₋₄alkyl,        C₁₋₁₀heteroaryl, C₁₋₁₀heteroaryloxy and C₁₋₁₀heterocycloxy;        wherein R^(2a) may, for each occurrence, be optionally        substituted with one or more substituents which are        independently selected from halo, hydroxy, C₁₋₄alkyl, and        C₁₋₄alkoxy; or    -   two R^(2a) on the same carbon atom taken together may form a        spiro C₃₋₇cycloalkyl which may be optionally substituted with        one or more substituent independently selected from halo,        hydroxy, C₁₋₄alkyl, and C₁₋₄alkoxy;    -   p is 0, 1 or 2;    -   X is CH₂;    -   Y is OH; or        a pharmaceutically acceptable salt thereof.

In another aspect of the invention, the compound of Formula (I) is ofFormula (I-iv):

-   -   wherein:    -   Ring A is a phenyl ring which is optionally substituted with one        substituent independently selected from the group consisting of        chloro, fluoro, methyl and methoxy; wherein Y_(a) is situated        meta to the tetrahydropyran ring and the one substituent is        situated para to the tetrahydropyran ring;    -   the structure represented by the following formula:

is selected from the group consisting of:

wherein the hydrogen on each nitrogen may be optionally replaced withR^(2a);

-   -   Y_(a) is CH₂;    -   V is OH;    -   n is 0 or 1;    -   q is 0 or 1;    -   R¹ and R^(1a) are each hydrogen;    -   R² is halo;    -   R^(2a), for each occurrence, is independently selected from the        group consisting of unsubstituted hydroxy and unsubstituted        C₁₋₂alkyl; and    -   X is CH₂;    -   Y is OH; or        a pharmaceutically acceptable salt thereof.

In another aspect of the invention, the compound of Formula (I) is ofFormula (I-iva):

-   -   wherein:    -   Ring A is a phenyl ring which is optionally substituted with one        substituent independently selected from the group consisting of        chloro, fluoro, hydroxy, cyano, methyl, ethyl, isopropyl,        ethynyl, methoxy, ethoxy, trifluoromethoxy, amino,        dimethylamino, methylsulfanyl, methylsulfonyl, carbamoyl,        cyclopropyl, cyclobutyl, phenyl, toulyl, phenoxy, oxazolyloxy,        and N-pyrazolyl; wherein Y_(a) is situated meta to the        tetrahydropyran ring and the one substituent is situated para to        the tetrahydropyran ring;    -   the structure represented by the following formula:

is selected from the group consisting of:

wherein the hydrogen on each nitrogen may be optionally replaced withR^(2a); R^(a), for each occurrence, is independently selected from halo,hydroxy, cyano, nitro, C₁₋₆alkyl, —S(O)_(p)R³, —C(O)OR³, —C(O)R³,—C(O)NR⁴R⁵, —NR⁴R⁵, —CH₂NR⁴R⁵ and C₁₋₆alkoxy; and m is 0 or an integerfrom 1-4;

-   -   p is 0, 1, or 2;    -   Y_(a) is CH₂;    -   V is OH;    -   n is 0 or 1;    -   q is 0 or 1;    -   R¹ and R^(1a) are each hydrogen;    -   R² is halo;    -   R^(2a), for each occurrence, is independently selected from the        group consisting of oxo, halo, hydroxy, cyano, nitro, C₁₋₆alkyl,        C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₄alkyl, C₆₋₁₀aryl,        C₆₋₁₀arylC₁₋₄alkyl, —C(O)OR³, —C(O)R³, —C(O)NR⁴R⁵, —NR⁴R⁵,        —CH₂NR⁴R⁵, C₁₋₆alkoxy, C₃₋₇ cycloalkoxy, —S(O)_(p)R³,        —S(O)₂NR⁴R⁵, —OS(O)₂R³, —CH₂C(O)OR³, —CH₂C(O)NR⁴R⁵,        —NR³C(O)NR⁴R⁵, —NR³C(O)OR³, C₆₋₁₀aryloxy, C₂₋₁₀heterocyclyl,        C₂₋₁₀heterocyclylC₁₋₄alkyl, C₁₋₁₀heteroarylC₁₋₄alkyl,        C₁₋₁₀heteroaryl, C₁₋₁₀heteroaryloxy and C₁₋₁₀heterocycloxy;        wherein R^(2a) may, for each occurrence, be optionally        substituted with one or more substituents which are        independently selected from halo, hydroxy, cyano, nitro,        C₁₋₆alkyl, —S(O)_(p)R³, —C(O)OR³, —C(O)R³, —C(O)NR⁴R⁵, —NR⁴R⁵,        —CH₂NR⁴R⁵ and C₁₋₆alkoxy;    -   X is CH₂; and    -   Y is OH; or        a pharmaceutically acceptable salt thereof.

In another aspect of the invention, the compound of Formula (I) is ofFormula (V):

-   -   wherein:    -   ring A is phenyl which is substituted with one substituent        selected from halo, C₁₋₄alkyl, and C₃₋₇cycloalkyl; wherein Y_(a)        is situated meta to the tetrahydropyran ring and the one        substituent is situated para to the tetrahydropyran ring;    -   the structure represented by the following formula:

-   -   Y_(a) is CH₂;    -   n is 0;    -   q is 0;    -   V is —OR^(1b);    -   X is CH₂;    -   Y is OR^(1c);    -   R¹, R^(1a), R^(1b) and R^(1c) are hydrogen;    -   or a pharmaceutically acceptable salt thereof.

Embodiments of the Compounds of Formulae (I), (I-a), (I-i), (I-ia),(I-ii), (I-iia), (I-iii), (I-iiia), (I-iv), (I-iva), and (V) General

Various embodiments of the invention are described herein. It will berecognised that features specified in each embodiment may be combinedwith other specified features to provide further embodiments. Thus,combinations of the various features are herein implicitly disclosed.

the Tetrahydropyran Ring and its Substituents

In one embodiment, V is OR^(1b). In a further embodiment, V is OH.

In one embodiment, R¹ and R^(1a) are independently selected fromhydrogen, C₁₋₃ alkyl, C₆₋₁₀aryl-C₁₋₄alkyl, —C(O)C₆₋₁₀aryl and—C(O)C₁₋₈alkyl. In a further embodiment, R¹ is H. In a furtherembodiment, R^(1a) is H. In a further embodiment, R¹ and R^(1a) are bothH.

In one embodiment, t is 1 or 2. In a further embodiment, t is 1.

In one embodiment, X is CH₂.

In one embodiment, Y is H or OR^(1c). In a further embodiment, Y is H orOH. In a further embodiment, Y is OH. In a further embodiment, Y is ahalo. In a further embodiment, Y is fluoro.

In one embodiment, the tetrahydropyran ring is a pyranose ring of thestructure:

In a further embodiment, the pyranose ring has the followingstereochemistry:

In one embodiment, R^(1b) is selected from hydrogen, C₁₋₃ alkyl,C₆₋₁₀aryl-C₁₋₄alkyl, —C(O)C₆₋₁₀aryl and —C(O)C₁₋₈alkyl. In a furtherembodiment, R^(1b) is H.

In one embodiment, R^(1c) is selected from hydrogen, C₁₋₃ alkyl,C₆₋₁₀aryl-C₁₋₄alkyl, —C(O)C₆₋₁₀aryl and —C(O)C₁₋₈alkyl. In a furtherembodiment, R^(1c) is H.

In one embodiment, R⁶ and R⁷, for each occurrence, are independentlyselected from hydrogen, C₁₋₃ alkyl, OR^(1e), and NR⁴R⁵; or when t is 1,R⁶ and R⁷ together may form an oxo group; or when R⁶ and R⁷ are on thesame carbon they can be taken together to form a C₃₋₇cycloalkyl or a 3-to 7-membered heterocycle. In a further embodiment, R⁶ and R⁷, for eachoccurrence, are independently selected from hydrogen and C₁₋₃ alkyl.

In one embodiment, R^(1e), for each occurrence, is independentlyselected from hydrogen, C₁₋₃ alkyl, C₆₋₁₀aryl-C₁₋₄alkyl, —C(O)C₆₋₁₀aryland —C(O)C₁₋₆alkyl. In a further embodiment, R^(1e), for eachoccurrence, is independently selected from hydrogen and C₁₋₃ alkyl.

Ring a and its Substituents

In one embodiment, Ring A is substituted with one or more substituentsindependently selected from the group consisting of halo, hydroxy,C₁₋₃alkyl, C₁₋₃alkoxy, haloC₁₋₃alkoxy and 5-membered heteroaryl. In afurther embodiment, Ring A is substituted with one or more substituentsindependently selected from the group consisting of halo, hydroxy,C₁₋₃alkyl, C₃₋₇cycloalkyl, C₁₋₃alkoxy, haloC₁₋₃alkoxy and 5-memberedheteroaryl. In a further embodiment, Ring A is substituted with one ormore substituents independently selected from the group consisting ofchloro, fluoro, hydroxy, methyl, methoxy, ethoxy, trifluoromethoxy andN-pyrazolyl. In a further embodiment, Ring A is substituted with one ormore substituents independently selected from the group consisting ofchloro, fluoro, hydroxy, methyl, ethyl, isopropyl, cyclopropyl, methoxy,ethoxy, trifluoromethoxy and N-pyrazolyl. In a further embodiment, RingA is substituted with one or more substituents independently selectedfrom the group consisting of chloro, fluoro, methyl and methoxy. In afurther embodiment, Ring A is substituted with one or more chlorosubstituents. In a further embodiment, Ring A is substituted with one ormore substituents independently selected from the group consisting ofchloro, ethyl, isopropyl, and cyclopropyl. In a further embodiment, RingA is substituted with one chloro. In a further embodiment, Ring A issubstituted with one ethyl. In a further embodiment, Ring A issubstituted with one isopropyl. In a further embodiment, Ring A issubstituted with one cyclopropyl.

In one embodiment, Ring A is naphthyl which is optionally substituted.

In a one embodiment, Ring A is phenyl which is optionally substituted.

In one embodiment, Y_(a) is situated meta to the tetrahydropyran ring.

In one embodiment, Ring A has one substituent. In one aspect of thisembodiment, Ring A has one substituent which is selected from the groupconsisting of halo, hydroxy, C₁₋₃alkyl, C₃₋₇cycloalkyl, C₁₋₃alkoxy,haloC₁₋₃alkoxy and 5-membered heteroaryl. In another aspect of thisembodiment, Ring A has one substituent which is selected from the groupconsisting of chloro, fluoro, hydroxy, methyl, ethyl, isopropyl,cyclopropyl, methoxy, ethoxy, trifluoromethoxy and N-pyrazolyl. Inanother aspect of this embodiment, Ring A is substituted with onechloro. In another aspect of this embodiment, Ring A is substituted withone ethyl. In another aspect of this embodiment, Ring A is substitutedwith one isopropyl. In another aspect of this embodiment, Ring A issubstituted with one cyclopropyl.

In a further embodiment, Ring A is unsubstituted.

In one embodiment, Ring A is phenyl with one substituent, Y_(a) issituated meta to the tetrahydropyran ring and the one substituent issituated para to the tetrahydropyran ring. In one aspect of thisembodiment, the substituent on Ring A is selected from the groupconsisting of halo, hydroxy, C₁₋₃alkyl, C₃₋₇cycloalkyl, C₁₋₃alkoxy,haloC₁₋₃alkoxy and 5-membered heteroaryl. In another aspect of thisembodiment, the substituent on Ring A is selected from the groupconsisting of chloro, fluoro, hydroxy, methyl, ethyl, isopropyl,cyclopropyl, methoxy, ethoxy, trifluoromethoxy and N-pyrazolyl. Inanother aspect of this embodiment, the substituent on Ring A is chloro.In another aspect of this embodiment, the substituent on Ring A isethyl. In another aspect of this embodiment, the substituent on Ring Ais isopropyl. In another aspect of this embodiment, the substituent onRing A is cyclopropyl.

Linker Y_(a)

In one embodiment, Y_(a) is a bond or a C₁₋₃alkylene.

In one embodiment, Y_(a) is unsubstituted.

In one embodiment, Y_(a) is CH₂.

the R² Substituent(s)

In one embodiment, R², for each occurrence, is independently selectedfrom the group consisting of halo, hydroxy, cyano, nitro, C₁₋₆alkyl,C₃₋₇cycloalkyl, C₆₋₁₀aryl, C₆₋₁₀arylC₁₋₄alkyl, —C(O)OR³, —C(O)R³,—C(O)NR⁴R⁵, —NR⁴R⁵, —CH₂NR⁴R⁵, C₁₋₆alkoxy, C₃₋₇ cycloalkoxy,—CH₂C(O)OR³, —CH₂C(O)NR⁴R⁵, —NR³C(O)NR⁴R⁵, —NR³C(O)OR³, C₆₋₁₀aryloxy,C₂₋₁₀heterocyclyl, C₁₋₁₀heteroaryl, C₁₋₁₀heteroaryloxy andC₁₋₁₀heterocycloxy. In a further embodiment, R², for each occurrence, isindependently selected from the group consisting of halo, hydroxy,cyano, nitro, C₁₋₃alkyl, C₃₋₇cycloalkyl, C₆₋₁₀aryl, C₆₋₁₀arylC₁₋₃alkyl,—C(O)OR³, —C(O)R³, —C(O)NR⁴R⁵, —NR⁴R⁵, —CH₂NR⁴R⁵, C₁₋₃alkoxy, C₃₋₇cycloalkoxy, —CH₂C(O)OR³, —CH₂C(O)NR⁴R⁵, —NR³C(O)NR⁴R⁵, —NR³C(O)OR³,C₆₋₁₀aryloxy, C₂₋₆heterocyclyl, C₅₋₇heteroaryl, C₅₋₇heteroaryloxy andC₂₋₆heterocycloxy.

In one embodiment, n is 0, 1 or 2. In a further embodiment, n is 0 or 1.In a further embodiment, n is 0.

In one embodiment, R² is halo and n is 1. In a further embodiment, R² isfluoro and n is 1.

Ring A′ and its Substituents

In one embodiment, Ring A′ contains at least one O or N heteroatom. In afurther embodiment, Ring A′ contains one or two heteroatoms, wherein theheteroatoms are independently O or N.

In one embodiment, Ring A′ contains at least one O, S or N heteroatom.In a further embodiment, Ring A′ contains one or two heteroatoms,wherein the heteroatoms are independently O, S, or N.

In one embodiment, Ring A′ is selected from the group consisting of amorpholine ring, a piperidine ring, a pyrrolidine ring, atetrahydropyran ring, a tetrahydrofuran ring and a 1,4-dioxane ring.

In one embodiment, Ring A′ is selected from the group consisting of amorpholine ring, a piperidine ring, and a 1,4-dioxane ring.

In one embodiment, the structure represented by the following formula:

is selected from the group consisting of:

wherein the hydrogen on each nitrogen may be optionally replaced withR^(2a).

In a further embodiment, the structure represented by the followingformula:

is selected from the group consisting of:

wherein the hydrogen on each nitrogen may be optionally replaced withR^(2a).

In one embodiment, the structure represented by the following formula:

is selected from the group consisting of:

wherein the hydrogen on each nitrogen may be optionally replaced withR^(2a).

In a further embodiment, the structure represented by the followingformula:

is selected from the group consisting of:

In one embodiment, R^(2a), for each occurrence, is independentlyselected from the group consisting of oxo, hydroxy, C₁₋₆alkyl,C₃₋₇cycloalkylC₁₋₄alkyl, C₆₋₁₀arylC₁₋₄alkyl, —C(O)OR³, —C(O)R³,—C(O)NR⁴R⁵ and CH₂C(O)OR³; wherein R^(2a) may, for each occurrence, beoptionally substituted with one or more substituents which areindependently selected from halo, hydroxy, C₁₋₄alkyl, and C₁₋₄alkoxy; or

-   -   two R^(2a) on adjacent atoms taken together with the atoms to        which they are attached may form a fused C₃₋₇cycloalkyl, C₆aryl,        3- to 7-membered heterocyclyl, or 5-membered heteroaryl, wherein        the fused cycloalkyl, aryl, heterocyclyl, and heteroaryl may be        optionally substituted with one or more substituent        independently selected from halo, hydroxy, C₁₋₄alkyl, and        C₁₋₄alkoxy; or    -   two R^(2a) on the same carbon atom taken together may form a        spiro 3- to 7-membered heterocyclyl or a spiro C₃₋₇cycloalkyl        which may be optionally substituted with one or more substituent        independently selected from halo, hydroxy, C₁₋₄alkyl, and        C₁₋₄alkoxy.

In a further embodiment, R^(2a), for each occurrence, is independentlyselected from the group consisting of oxo, halo, hydroxy, cyano, nitro,C₁₋₆alkyl, C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₄alkyl, C₆₋₁₀aryl,C₆₋₁₀arylC₁₋₄alkyl, —C(O)OR³, —C(O)R³, —C(O)NR⁴R⁵, —NR⁴R⁵, —CH₂NR⁴R⁵,C₁₋₆alkoxy, C₃₋₇ cycloalkoxy, —S(O)_(p)R³, —S(O)₂NR⁴R⁵, —OS(O)₂R³,—CH₂C(O)OR³, —CH₂C(O)NR⁴R⁵, —NR³C(O)NR⁴R⁵, —NR³C(O)OR³, C₆₋₁₀aryloxy,C₂₋₁₀heterocyclyl, C₂₋₁₀heterocyclylC₁₋₄alkyl, C₁₋₁₀heteroarylC₁₋₄alkyl,C₁₋₁₀heteroaryl, C₁₋₁₀heteroaryloxy and C₁₋₁₀heterocycloxy; whereinR^(2a) may, for each occurrence, be optionally substituted with one ormore substituents which are independently selected from halo, hydroxy,cyano, nitro, C₁₋₆alkyl, —S(O)_(p)R³, —C(O)OR³, —C(O)R³, —C(O)NR⁴R⁵,—NR⁴R⁵, —CH₂NR⁴R⁵ and C₁₋₆alkoxy; or

-   -   two R^(2a) on adjacent atoms taken together with the atoms to        which they are attached may form a fused C₃₋₇cycloalkyl, C₆aryl,        3- to 7-membered heterocyclyl, or 5-membered heteroaryl, wherein        the fused cycloalkyl, aryl, heterocyclyl, and heteroaryl may be        optionally substituted with one or more substituent        independently selected from halo, hydroxy, C₁₋₄alkyl, and        C₁₋₄alkoxy; or    -   two R^(2a) on the same carbon atom taken together may form a        spiro 3- to 7-membered heterocyclyl or a spiro C₃₋₇cycloalkyl        which may be optionally substituted with one or more substituent        independently selected from halo, hydroxy, C₁₋₄alkyl, and        C₁₋₄alkoxy.

In a further embodiment, R^(2a), for each occurrence, is independentlyselected from the group consisting of hydroxy, C₁₋₆alkyl,C₃₋₇cycloalkylC₁₋₄alkyl; wherein R^(2a) may, for each occurrence, beoptionally substituted with one or more substituents which areindependently selected from halo, hydroxy, C₁₋₄alkyl, and C₁₋₄alkoxy; or

-   -   two R^(2a) on the same carbon atom taken together may form a        spiro C₃₋₇cycloalkyl which may be optionally substituted with        one or more substituent independently selected from halo,        hydroxy, C₁₋₄alkyl, and C₁₋₄alkoxy.

In a further embodiment, R^(2a), for each occurrence, is independentlyselected from the group consisting of unsubstituted hydroxy andunsubstituted C₁₋₂alkyl.

In one embodiment, q is 0, 1 or 2. In a further embodiment, q is 0 or 1.In a further embodiment, q is 0.

Groups R³, R⁴ and R⁵

In one embodiment, R³, for each occurrence, is independently selectedfrom hydrogen, C₁₋₃ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylC₁₋₃alkyl,C₆₋₁₀aryl, C₁₋₇heteroaryl, and C₂₋₈heterocyclyl. In a furtherembodiment, R³, for each occurrence, is independently selected fromhydrogen and C₁₋₃ alkyl.

In one embodiment, R⁴ and R⁵, for each occurrence, are independentlyselected from hydrogen, C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₃₋₇cycloalkylC₁₋₄alkyl, C₆₋₁₀arylC₁₋₄alkyl, C₆₋₁₀aryl, C₁₋₁₀heteroaryl,C₁₋₁₀heteroarylC₁₋₄alkyl, C₂₋₁₀heterocyclyl, andC₂₋₁₀heterocyclylC₁₋₄alkyl; or R⁴ and R⁵ taken together along with thenitrogen to which they are bound may form a monocyclic or a bicyclicheteroaryl (with 5 to 14 members and having 1 to 8 heteroatoms selectedfrom N, O and S) or heterocyclyl (which is a 4 to 7 membered monocyclicring or a 7 to 12 membered bicyclic ring or a 10 to 15 memberedtricyclic ring having at least one heteroatom selected from N, O and S)which may be optionally substituted with one or more halo or C₁₋₄alkylsubstituent.

In a further embodiment, R⁴ and R⁵, for each occurrence, areindependently selected from hydrogen, C₁₋₃ alkyl, C₃₋₇ cycloalkyl, C₃₋₇cycloalkylC₁₋₃alkyl, C₆₋₁₀arylC₁₋₄alkyl, C₆₋₁₀aryl, C₁₋₇heteroaryl,C₁₋₇heteroarylC₁₋₃alkyl, C₂₋₈heterocyclyl, andC₂₋₈heterocyclylC₁₋₃alkyl; or R⁴ and R⁵ taken together along with thenitrogen to which they are bound may form a monocyclic or a bicyclicheteroaryl or heterocyclyl which may be optionally substituted with oneor more halo or C₁₋₃alkyl. In a further embodiment, R⁴ and R⁵, for eachoccurrence, are independently selected from hydrogen and C₁₋₃ alkyl.

Further Embodiments

In one embodiment, the moiety

is selected from any one of structures i to xiv below.

In one embodiment, the moiety

is selected from any one of structures (ii), (vii) and (xv) below.

In a further embodiment, the moiety

is selected from any one of structures i, ii, vi, viii, ix and xi to xivabove.

Specific Compounds

In another aspect of the invention, there is provided a compoundselected from compounds 1 to 72 below, or a pharmaceutically acceptablesalt thereof:

-   1. (2S,3R,4R,5S,6R)-2-[4-Chloro-3-(4-methyl-3,4-dihydro-2H    benzo[1,4]oxazin-7-ylmethyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol-   2.    (2S,3R,4R,5S,6R)-2-[4-Chloro-3-(4-ethyl-3,4-dihydro-2H-benzo[1,4]oxazin-7-ylmethyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol-   3.    (2S,3R,4R,5S,6R)-2-[4-Chloro-3-(4-cyclopropyl-3,4-dihydro-2Hbenzo[1,4]oxazin-7ylmethyl)-phenyl]-6-hydroxymethyltetrahydropyran3,4,5-triol-   4.    (2S,3R,4R,5S,6R)-2-[3-(4-Benzyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-4-chloro-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol-   5.    (2S,3R,4R,5S,6R)-2-{4-Chloro-3-[4-(4-methoxy-benzyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl]-phenyl}-6-hydroxymethyltetrahydro-pyran-3,4,5-triol-   6.    (2S,3R,4R,5S,6R)-2-[3-(4-Benzyl-2,2-dimethyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-4-chloro-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol-   7.    (2S,3R,4R,5S,6R)-2-[3-(4-benzyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-4-chloro-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol-   8.    (2S,3R,4R,5S,6R)-2-[4-Chloro-3-(3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol-   9.    (2S,3R,4R,5S,6R)-2-[4-Chloro-3-(4-ethyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol-   10.    (2S,3R,4R,5S,6R)-2-[4-Chloro-3-(4-cyclopropylmethyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol-   11.    (2S,3R,4R,5S,6R)-2-[4-Chloro-3-(4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol-   12.    6-[2-Chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yl)-benzyl]-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic    acid ethyl ester-   13.    1-{6-[2-Chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yl)-benzyl]-2,3-dihydro-benzo[1,4]oxazin-4-yl}-ethanone-   14.    (2S,3R,4R,5S,6R)-2-{4-Chloro-3-[1-(4-methoxy-benzyl)-1,2,3,4-tetrahydro-quinolin-6-ylmethyl]-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol-   15.    (2S,3R,4R,5S,6R)-2-[4-Chloro-3-(1,2,3,4-tetrahydro-quinolin-6-ylmethyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol-   16.    (2S,3R,4R,5S,6R)-2-[4-Chloro-3-(1,2,3,4-tetrahydro-quinolin-7-ylmethyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol-   17.    (2S,3R,4R,5S,6R)-2-[4-Chloro-3-(2,3-dihydro-1H-indol-5-ylmethyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol-   18.    (2S,3R,4R,5S,6R)-2-[3-(2-Benzyl-1,2,3,4-tetrahydro-isoquinolin-7-ylmethyl)-4-chloro-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol-   19.    (2S,3R,4R,5S,6R)-2-[4-Chloro-3-(1,2,3,4-tetrahydro-isoquinolin-7-ylmethyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol-   20.    (2S,3R,4R,5S,6R)-2-[4-Chloro-3-(2,2-dimethyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol-   21.    (2S,3R,4R,5S,6R)-2-(4-Chloro-3-chroman-6-ylmethyl-phenyl)-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol-   22.    (2S,3R,4R,5S,6R)-2-[4-Chloro-3-(2,3-dihydro-benzofuran-5-ylmethyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol-   23.    (2R,3S,4R,5R,6S)-2-Hydroxymethyl-6-[4-methyl-3-(1,2,3,4-tetrahydro-quinolin-7-ylmethyl)-phenyl]-tetrahydro-pyran-3,4,5-triol-   24.    (2S,3R,4R,5S,6R)-2-[3-(3,4-Dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-4-fluoro-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol-   25.    (2S,3R,4R,5S,6R)-2-[3-(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-methoxy-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol-   26.    (2R,3S,4R,5R,6S)-2-Hydroxymethyl-6-[4-methoxy-3-(1,2,3,4-tetrahydro-quinolin-6-ylmethyl)-phenyl]-tetrahydro-pyran-3,4,5-triol-   27.    (2R,3S,4R,5R,6S)-2-Hydroxymethyl-6-[4-methoxy-3-(1,2,3,4-tetrahydro-quinolin-7-ylmethyl)-phenyl]-tetrahydro-pyran-3,4,5-triol-   28.    (2S,3R,4R,5S,6R)-2-[4-Chloro-3-(3,4-dihydro-2H-benzo[1,4]oxazin-7-ylmethyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol-   29.    (2S,3R,4R,5S,6R)-2-[4-Chloro-3-(4,4-spiro-cyclopropyl-chroman-6-ylmethyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol-   30.    2S,3R,4R,5S,6R)-2-[5-(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-2-ethoxy-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol-   31.    (2S,3R,4R,5S,6R)-2-[3-(3,4-Dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-4-methoxy-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol-   32.    (2S,3R,4R,5S,6R)-2-(3-Chroman-6-ylmethyl-4-methoxy-phenyl)-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol-   33.    (2S,3R,4R,5S,6R)-2-(3-Chroman-6-ylmethyl-4-trifluoromethoxy-phenyl)-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol-   34.    6-[2-chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yl)-benzyl]-chromen-4-one-   35.    6-[2-Chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yl)-benzyl]-chroman-4-one-   36.    (2S,3R,4R,5S,6R)-2-[4-Chloro-3-(4-hydroxy-chroman-6-ylmethyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol-   37.    (2S,3R,4R,5S,6R)-2-[4-Chloro-3-(spiro[chromane-2,1′-cyclopentane]-6-ylmethyl)phenyl]-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol-   38.    (2S,3R,4R,5S,6R)-2-[4-Chloro-3-(spiro[chromane-2,1′-cyclopentane]-6-ylmethyl)phenyl]-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol-   39.    6-[[2-Chloro-5-[(2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydropyran-2-yl]phenyl]methyl]spiro[chromane-2,4′-piperidine]-4-one-   40.    6-(2-Methoxy-5-((2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6(benzyloxymethyl)tetrahydro-2H-pyran-2-yl)benzyl)spiro[chroman-2,1′-cyclobutane-   41.    (2S,3R,4R,5S,6R)-2-[4-methoxy-3-(spiro[chromane-2,1′-cyclobutane]-6-ylmethyl)phenyl]-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol-   42.    7-[2-Chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yl)-benzyl]-4H-benzo[1,4]oxazin-3-one-   43.    7-[2-Methoxy-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yl)-benzyl]-4H-benzo[1,4]oxazin-3-one-   44.    (2S,3R,4R,5S,6R)-2-[4-chloro-3-(spiro[chromane-2,1′-cyclobutane]-6-ylmethyl)phenyl]-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol-   45.    [(2R,3R,4R,5S,6S)-3,4,5-triacetoxy-6-[4-chloro-3-[(2,2-dimethyl-3-oxo-4H-1,4-benzoxazin-6-yl)methyl]phenyl]tetrahydropyran-2-yl]methyl    acetate-   46.    6-[2-Chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yl)-benzyl]-2,2-dimethyl-4H-benzo[1,4]oxazin-3-one-   47.    6-(2-chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)benzyl)-2H-benzo[b][1,4]oxazin-3(4H)-one-   48.    (2S,3R,4R,5S,6R)-2-[3-[(4-benzylspiro[3H-1,4-benzoxazine-2,1′-cyclopropane]-6-yl)methyl]-4-chloro-phenyl]-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol-   49.    (2S,3R,4R,5S,6R)-2-[4-Chloro-3-(spiro[3,4-dihydro-1,4-benzoxazine-2,1′-cyclopropane]-6-ylmethyl)phenyl]-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol-   50. Acetic acid    (2R,3R,4R,5S,6S)-3,4,5-triacetoxy-6-[4-chloro-3-(2-cyano-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-phenyl]-tetrahydro-pyran-2-ylmethyl    ester-   51.    6-[2-Chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yl)-benzyl]-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonitrile-   52.    6-[2-chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yl)-benzyl]-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic    acid methyl ester-   53.    6-[2-Chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yl)-benzyl]-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic    acid-   54.    6-[2-bromo-5-((3S,4R,5R,6R)-3,4,5-tris-benzyloxy-6-benzyloxymethyl-tetrahydro-pyran-2-yl)-benzyl]-chroman-   55.    6-[2-cyclopropyl-5-((3S,4R,5R,6R)-3,4,5-tris-benzyloxy-6-benzyloxymethyl-tetrahydro-pyran-2-yl)-benzyl]-chroman-   56.    (2S,3R,4R,5S,6R)-2-(3-Chroman-6-ylmethyl-4-cyclopropyl-phenyl)-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol-   57.    [(2R,3R,4R,5S,6S)-3,4,5-triacetoxy-6-[4-bromo-3-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)phenyl]tetrahydropyran-2-yl]methyl    acetate-   58.    [(2R,3R,4R,5S,6S)-3,4,5-triacetoxy-6-[4-bromo-3-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)phenyl]tetrahydropyran-2-yl]methyl    acetate-   59. Acetic acid    (2R,3R,4R,5S)-3,4,5-triacetoxy-6-[4-cyclopropyl-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-tetrahydro-pyran-2-ylmethyl    ester-   60.    (2S,3R,4R,5S,6R)-2-[4-Cyclopropyl-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol-   61. Acetic acid    (2R,3R,4R,5S)-3,4,5-triacetoxy-6-[3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-tetrahydro-pyran-2-ylmethyl    ester-   62.    (2S,3R,4R,5S,6R)-2-[3-(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol-   63.    4-Benzyl-6-[2-bromo-5-((2S,3S,4R,5R,6R)-3,4,5-tris-benzyloxy-6-benzyloxymethyl-tetrahydro-pyran-2-yl)-benzyl]-3,4-dihydro-2H-benzo[1,4]oxazine-   64.    4-Benzyl-6-[2-cyclopropyl-5-((2S,3S,4R,5R,6R)-3,4,5-tris-benzyloxy-6-benzyloxymethyl-tetrahydro-pyran-2-yl)-benzyl]-3,4-dihydro-2H-benzo[1,4]oxazine-   65.    (2S,3R,4R,5S,6R)-2-[4-Cyclopropyl-3-(3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol-   66.    (2S,3R,4R,5S,6R)-2-[3-(3,4-Dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-4-ethyl-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol-   67.    (2S,3R,4R,5S,6R)-2-[2-(3,4-Dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-4′-methyl-biphenyl-4-yl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol-   68.    (2S,3R,4R,5S,6R)-2-[3-(4-Benzyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-4-isopropyl-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol-   69.    (2S,3R,4R,5S,6R)-2-[3-(3,4-Dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-4-isopropyl-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol-   70.    (2S,3R,4R,5S,6R)-2-[3-(1-Benzyl-1,2,3,4-tetrahydro-quinolin-7-ylmethyl)-4-isopropyl-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol-   71.    (2R,3S,4R,5R,6S)-2-Hydroxymethyl-6-[4-isopropyl-3-(1,2,3,4-tetrahydro-quinolin-7-ylmethyl)-phenyl]-tetrahydro-pyran-3,4,5-triol-   72.    (2R,3S,4R,5R,6S)-2-Hydroxymethyl-6-[4-isopropyl-3-(1,2,3,4-tetrahydro-quinolin-6-ylmethyl)-phenyl]-tetrahydro-pyran-3,4,5-triol

In another aspect of the invention, there is provided a compoundselected from compounds 1 to 72 and compounds 73 to 126 below, or apharmaceutically acceptable salt thereof:

-   73    (2S,3R,4R,5S,6R)-2-(3-Chroman-6-ylmethyl-4-methyl-phenyl)-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol-   74    (2S,3R,4R,5S,6R)-2-(3-Chroman-6-ylmethyl-4-hydroxy-phenyl)-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol-   75    (2S,3R,4R,5S,6R)-2-(3-Chroman-6-ylmethyl-4-ethoxy-phenyl)-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol-   76    (2S,3R,4R,5S,6R)-2-(3-Chroman-6-ylmethyl-4-pyrazol-1-yl-phenyl)-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol-   77    (2S,3R,4R,5S,6R)-2-(3-Chroman-6-ylmethyl-2-hydroxy-4-methyl-phenyl)-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol-   78    (2S,3R,4R,5S,6R)-2-[3-(3,4-Dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-4-hydroxy-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol-   79    (2S,3R,4R,5S,6R)-2-[3-(3,4-Dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-4-ethoxy-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol-   80    (2S,3R,4R,5S,6R)-2-[3-(3,4-Dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-4-pyrazol-1-yl-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol-   81    2S,3R,4R,5S,6R)-2-[3-(3,4-Dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-2-hydroxy-4-methyl-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol-   82    (2S,3R,4R,5S,6R)-2-[3-(3,4-Dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-2-hydroxy-4-methyl-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol-   83    (2R,3S,4R,5R,6S)-2-(hydroxymethyl)-6-[4-methyl-3-(spiro[chromane-4,1′-cyclopropane]-6-ylmethyl)phenyl]tetrahydropyran-3,4,5-triol-   84    (2S,3R,4R,5S,6R)-2-[4-ethoxy-3-(spiro[3,4-dihydro-1,4-benzoxazine-2,1′-cyclopentane]-6-ylmethyl)phenyl]-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol-   85    (2S,3R,4R,5S,6R)-2-[4-chloro-3-(spiro[3,4-dihydro-1,4-benzoxazine-2,1′-cyclopropane]-6-ylmethyl)phenyl]-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol-   86    (2R,3S,4R,5R,6S)-2-Hydroxymethyl-6-[4-methyl-3-(1-methyl-1,2,3,4-tetrahydro-quinolin-6-ylmethyl)-phenyl]-tetrahydro-pyran-3,4,5-triol-   87    6-[2-Chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yl)-benzyl]-chroman-2-carboxylic    acid amide-   88    {6-[2-Chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yl)-benzyl]-2,3-dihydro-benzo[1,4]oxazin-4-yl}-acetic    acid-   89    (2S,3R,4R,5S,6R)-2-[4-Chloro-3-(1-methyl-1,4-dihydro-chromeno[4,3-b]pyrrol-8-ylmethyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol-   90    (2S,3R,4R,5S,6R)-2-[4-Chloro-3-(1,1a,2,7a-tetrahydro-7-oxa-cyclopropa[b]naphthalen-4-ylmethyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol-   91    (2S,3R,4R,5S,6R)-2-[4-Chloro-3-(8-fluoro-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol-   92    (2S,3R,4R,5S,6R)-2-[4-Chloro-3-(8-fluoro-2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol-   93    6-[2-Chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yl)-benzyl]-1-methyl-3,4-dihydro-1H-quinolin-2-one-   94    (2S,3R,4R,5S,6R)-2-[4-Chloro-3-(2-methyl-2,3-dihydro-1H-isoindol-5-ylmethyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol-   95    (2S,3R,4R,5S,6R)-2-[4-chloro-3-(spiro[cyclopropane-1,4′-isochromane]-7′-ylmethyl)phenyl]-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol-   96    (2R,3S,4S,5R,6S)-2-methyl-6-[4-methyl-3-(spiro[chromane-4,1′-cyclopropane]-6-ylmethyl)phenyl]tetrahydropyran-3,4,5-triol-   97    (2S,3R,4S,5S,6R)-2-[4-chloro-3-(spiro[chromane-2,3′-pyrrolidine]-6-ylmethyl)phenyl]-6-methyl-tetrahydropyran-3,4,5-triol-   98    (2S,3R,4S,5S,6R)-2-[4-chloro-3-(spiro[3,4-dihydro-1,4-benzoxazine-2,1′-cyclopentane]-6-ylmethyl)phenyl]-6-methyl-tetrahydropyran-3,4,5-triol-   99    (2S,3R,4R,5S,6S)-2-[4-chloro-3-(spiro[3,4-dihydro-1,4-benzoxazine-2,1′-cyclopentane]-6-ylmethyl)phenyl]-6-(fluoromethyl)tetrahydropyran-3,4,5-triol-   100    (2S,3R,4R,5S,6R)-2-[4-chloro-3-(spiro[3,4-dihydro-1,4-benzoxazine-2,1′-cyclopropane]-6-ylmethyl)phenyl]-6-(1-hydroxyethyl)tetrahydropyran-3,4,5-triol-   101    (2S,3R,4S,5S,6R)-2-[4-chloro-3-(2,4-dihydrochromeno[4,3-c]pyrazol-8-ylmethyl)phenyl]-6-ethyl-tetrahydropyran-3,4,5-triol-   102    (2S,3R,4S,5S,6R)-2-[4-chloro-3-(1H-phenoxazin-2-ylmethyl)phenyl]-6-methyl-tetra    hydropyran-3,4,5-triol-   103    (2S,3R,4R,5S,6R)-2-[3-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-4-isopropyl-phenyl]-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol-   104    (2S,3R,4R,5S,6R)-2-[3-(chroman-6-ylmethyl)-4-cyclobutyl-phenyl]-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol-   105    (2S,3R,4R,5S,6R)-2-[4-ethyl-3-(1,2,3,4-tetrahydroquinolin-7-ylmethyl)phenyl]-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol-   106    (2S,3R,4R,5S,6R)-2-[4-cyclopropyl-3-(1,2,3,4-tetrahydroquinolin-7-ylmethyl)phenyl]-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol-   107    (2S,3R,4R,5S,6R)-2-[3-(3,4-dihydro-2H-1,4-benzothiazin-6-ylmethyl)-4-methoxy-phenyl]-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol-   108    (2S,3R,4R,5S,6R)-2-[4-chloro-3-(3,4-dihydro-2H-1,4-benzothiazin-6-ylmethyl)phenyl]-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol-   109    (2S,3R,4R,5S,6R)-2-[3-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-4-ethynyl-phenyl]-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol-   110    (2S,3R,4R,5S,6R)-2-[4-ethyl-3-(1,2,3,4-tetrahydroquinolin-6-ylmethyl)phenyl]-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol-   111    (2S,3R,4R,5S,6R)-2-[4-ethyl-3-(1,2,3,4-tetrahydroquinolin-6-ylmethyl)phenyl]-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol-   112    (2S,3R,4R,5S,6R)-2-[3-(3,4-dihydro-2H-1,4-benzothiazin-6-ylmethyl)-4-methoxy-phenyl]-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol-   113    (2S,3R,4R,5S,6R)-2-[4-chloro-3-(3,4-dihydro-2H-1,4-benzothiazin-6-ylmethyl)phenyl]-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol-   114    (2S,3R,4R,5S,6R)-2-[3-(chroman-6-ylmethyl)-4-methylsulfanyl-phenyl]-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol-   115    (2S,3R,4R,5S,6R)-2-[3-(chroman-6-ylmethyl)-4-methylsulfonyl-phenyl]-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol-   116    (2S,3R,4R,5S,6R)-2-[4-cyclopropyl-3-(1,2,3,4-tetrahydroquinolin-6-ylmethyl)phenyl]-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol-   117    (2S,3R,4R,5S,6R)-2-[3-(3,4-dihydro-2H-1,4-benzoxazin-6-ylmethyl)-4-dimethylamino-phenyl]-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol-   118    (2S,3R,4R,5S,6R)-2-[4-amino-3-(3,4-dihydro-2H-1,4-benzoxazin-6-ylmethyl)phenyl]-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol-   119    (2S,3R,4R,5S,6R)-2-[3-(3,4-dihydro-2H-1,4-benzothiazin-6-ylmethyl)-4-methoxy-phenyl]-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol-   120    (2S,3R,4R,5S,6R)-2-[3-[(1,1-dioxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)methyl]-4-methoxy-phenyl]-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol-   121    3-chloro-2-(3,4-dihydro-2H-1,4-benzoxazin-6-ylmethyl)-6-[(2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydropyran-2-yl]benzamide-   122    2-(2,3-dihydro-1,4-benzodioxin-7-ylmethyl)-4-[(2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydropyran-2-yl]benzonitrile-   123    (2S,3R,4R,5S,6R)-2-[3-(2,3-dihydro-1,4-benzodioxin-7-ylmethyl)-4-ethynyl-phenyl]-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol-   124    (2S,3R,4R,5S,6R)-2-[3-(3,4-dihydro-2H-1,4-benzoxazin-6-ylmethyl)-4-phenoxy-phenyl]-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol-   125    (2S,3R,4R,5S,6R)-2-[3-(3,4-dihydro-2H-1,4-benzoxazin-6-ylmethyl)-4-oxazol-4-yloxy-phenyl]-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol-   126 (1R,2R,3S,4S,6R)-4-[3-(9a,    10-dihydro-5aH-phenothiazin-3-ylmethyl)-4-chloro-phenyl]-6-(hydroxymethyl)cyclohexane-1,2,3-triol    -   or a pharmaceutically acceptable salt thereof.

Preferably, the compound is compound 40, 39, 30, 16, 14, 1, 7, 15, 13,27, 20, 8, 10, 21 or 19, or a pharmaceutically acceptable salt thereof.

More preferably, the compound is example 8, or a pharmaceuticallyacceptable salt thereof.

More preferably, the compound is example 60, or a pharmaceuticallyacceptable salt thereof.

More preferably, the compound is example 62, or a pharmaceuticallyacceptable salt thereof.

More preferably, the compound is example 71, or a pharmaceuticallyacceptable salt thereof.

Compounds of Formula (I), (I-a), (I-i), (I-ia), (1-ii), (I-iia),(1-iii), (I-iiia), (I-iv), (I-iva), and (V) and Derivatives Thereof

As used herein, the terms “compound of the invention” and “compound ofFormula (I)” etc. include pharmaceutically acceptable derivativesthereof and polymorphs, isomers and isotopically labelled variantsthereof. Furthermore, the term “compounds of the invention” and“compound of Formula (I)” etc. include compounds of formulae (I), (I-a),(I-i), (I-ia), (I-ii), (I-iia), (I-iii), (I-iiia), (I-iv), (I-iva), and(V), and the embodiments thereof disclosed herein.

Pharmaceutically Acceptable Derivatives

The term “pharmaceutically acceptable derivative” includes anypharmaceutically acceptable salt, solvate, or hydrate of a compound ofFormula (I).

Pharmaceutically Acceptable Salts

The term “pharmaceutically acceptable salt” includes a salt preparedfrom pharmaceutically acceptable non-toxic acids or bases includinginorganic or organic acids and bases.

Compounds of Formula (I) which contain basic, e.g. amino, groups arecapable of forming pharmaceutically acceptable salts with acids. In oneembodiment, pharmaceutically acceptable acid addition salts of thecompounds of Formula (I) include, but are not limited to, those ofinorganic acids such as hydrohalic acids (e.g. hydrochloric, hydrobromicand hydroiodic acid), sulfuric acid, nitric acid, and phosphoric acids.In one embodiment, pharmaceutically acceptable acid addition salts ofthe compounds of Formula (I) include, but are not limited to, those oforganic acids such as aliphatic, aromatic, carboxylic and sulfonicclasses of organic acids, examples of which include: aliphaticmonocarboxylic acids such as formic acid, acetic acid, propionic acid orbutyric acid; aliphatic hydroxy acids such as lactic acid, citric acid,tartaric acid or malic acid; dicarboxylic acids such as maleic acid orsuccinic acid; aromatic carboxylic acids such as benzoic acid,p-chlorobenzoic acid, phenylacetic acid, diphenylacetic acid ortriphenylacetic acid; aromatic hydroxyl acids such as o-hydroxybenzoicacid, p-hydroxybenzoic acid, 1-hydroxynaphthalene-2-carboxylic acid or3-hydroxynaphthalene-2-carboxylic acid; and sulfonic acids such asmethanesulfonic acid, ethanesulfonic acid or benzenesulfonic acid. Otherpharmaceutically acceptable acid addition salts of the compounds ofFormula (I) include, but are not limited to, those of glycolic acid,glucuronic acid, furoic acid, glutamic acid, anthranilic acid, salicylicacid, mandelic acid, embonic (pamoic) acid, pantothenic acid, stearicacid, sulfanilic acid, algenic acid, and galacturonic acid.

Compounds of Formula (I) which contain acidic, e.g. carboxyl, groups arecapable of forming pharmaceutically acceptable salts with bases. In oneembodiment, pharmaceutically acceptable basic salts of the compounds ofFormula (I) include, but are not limited to, metal salts such as alkalimetal or alkaline earth metal salts (e.g. sodium, potassium, magnesiumor calcium salts) and zinc or aluminium salts. In one embodiment,pharmaceutically acceptable basic salts of the compounds of Formula (I)include, but are not limited to, salts formed with ammonia orpharmaceutically acceptable organic amines or heterocyclic bases such asethanolamines (e.g. diethanolamine), benzylamines, N-methyl-glucamine,amino acids (e.g. lysine) or pyridine.

Hemisalts of acids and bases may also be formed, e.g. hemisulphatesalts.

Pharmaceutically acceptable salts of compounds of Formula (I) may beprepared by methods well-known in the art.

For a review of pharmaceutically acceptable salts, see Stahl andWermuth, Handbook of Pharmaceutical Salts: Properties, Selection and Use(Wiley-VCH, Weinheim, Germany, 2002).

Solvates & hydrates

The compounds of the invention may exist in both unsolvated and solvatedforms. The term “solvate” includes molecular complexes comprising acompound of the invention and one or more pharmaceutically acceptablesolvent molecules such as water or C₁₋₆ alcohols, e.g. ethanol. The term“hydrate” means a “solvate” where the solvent is water. Thus, thecompounds of the present invention may exist as a hydrate, including amonohydrate, dihydrate, hemihydrate, sesquihydrate, trihydrate,tetrahydrate and the like, as well as the corresponding solvated forms.The compound of the invention may be true solvates, while in othercases, the compound of the invention may merely retain adventitiouswater or be a mixture of water plus some adventitious solvent.

Amorphous & Crystalline Forms

The compounds of the invention may exist in solid states from amorphousthrough to crystalline forms. All such solid forms are included withinthe invention.

Co-Crystalline Forms

The compounds of the invention may exist as co-crystals. All suchco-crystalline forms are included within the invention. In oneembodiment, the compounds of the invention exist as co-crystals withL-proline.

For the avoidance of doubt, the terms “L-proline co-crystal of acompound of the invention”, such as an L-proline co-crystal of(2S,3R,4R,5S,6R)-2-[4-Chloro-3-(3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol,an L-proline co-crystal of(2S,3R,4R,5S,6R)-2-[4-Cyclopropyl-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol,an L-proline co-crystal of(2S,3R,4R,5S,6R)-2-[3-(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol,or an L-proline co-crystal of(2R,3S,4R,5R,6S)-2-Hydroxymethyl-6-[4-isopropyl-3-(1,2,3,4-tetrahydro-quinolin-7-ylmethyl)-phenyl]-tetrahydro-pyran-3,4,5-triol,refers to all forms of association between L-proline and a compound ofthe invention, including salt forms. In particular, these termsencompass: (i) a non-ionic association between L-proline and a compoundof the invention (i.e. where no proton transfer has occurred betweenL-proline and a compound of the invention); or (ii) an ionic interactionwhere proton transfer between L-proline and a compound of the inventionhas occurred to form an L-proline salt of the compound of the invention,or (iii) mixtures of (i) and (ii) above.

In a particular embodiment of the invention, the L-proline co-crystalcomprises is a non-ionic association between a compound of the inventionand L-proline (i.e. where no proton transfer has occurred betweenL-proline and the compound of the invention).

In an alternative embodiment of the invention, the L-proline co-crystalis an L-proline salt of the compound of the invention.

In one embodiment, the invention provides a crystalline form ofL-proline co-crystal of(2S,3R,4R,5S,6R)-2-[4-Chloro-3-(3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol.In one aspect, the crystalline form is non-ionic. In another aspect, thecrystalline form has differential scanning calorimetry endotherms atabout 64° C., about 104° C. and/or about 157° C. In another aspect, thecrystalline form has a molar ratio of L-proline to(2S,3R,4R,5S,6R)-2-[4-Chloro-3-(3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triolof 1:1. In another aspect, the crystalline form has powder X-raydiffraction peak(s) at about 19.3, about 23.2, about 17.0, and/or about5.7 degrees 20. In one aspect, the crystalline form has powder X-raydiffractions peaks substantially the same as those listed in Table 1A.

In one embodiment, the invention provides a crystalline form ofL-proline co-crystal of(2S,3R,4R,5S,6R)-2-[4-Cyclopropyl-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol.In one aspect, the crystalline form is non-ionic. In another aspect, thecrystalline form has differential scanning calorimetry endotherms atabout 151° C. In another aspect, the crystalline form has a molar ratioof L-proline to(2S,3R,4R,5S,6R)-2-[4-Cyclopropyl-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triolof 1:1. In another aspect, the crystalline form has powder X-raydiffraction peak(s) at about 16.7, about 19.9, about 17.6, and/or about21.9 degrees 20. In one aspect, the crystalline form has powder X-raydiffractions peaks substantially the same as those listed in Table 2A.

In one embodiment, the invention provides a crystalline form ofL-proline co-crystal of(2S,3R,4R,5S,6R)-2-[3-(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol.In one aspect, the crystalline form is non-ionic. In another aspect, thecrystalline form has differential scanning calorimetry endotherms atabout 136° C. In another aspect, the crystalline form has a molar ratioof L-proline to(2S,3R,4R,5S,6R)-2-[3-(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triolof 1:1. In another aspect, the crystalline form has powder X-raydiffraction peak(s) at about 17.3, about 20.4, about 18.0, about 18.9,and/or about 23.8 degrees 20. In one aspect, the crystalline form haspowder X-ray diffractions peaks substantially the same as those listedin Table 3A. In another aspect, the crystalline form has a powder X-raydiffraction spectrum substantially the same as the spectrum shown inFIG. 2. In another aspect, the crystalline form has a molar ratio ofL-proline to(2S,3R,4R,5S,6R)-2-[3-(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triolof 2:1. In another aspect, the crystalline form has differentialscanning calorimetry endotherms at about 176° C.

In one embodiment, the invention provides a crystalline form ofL-proline co-crystal of(2R,3S,4R,5R,6S)-2-Hydroxymethyl-6-[4-isopropyl-3-(1,2,3,4-tetrahydro-quinolin-7-ylmethyl)-phenyl]-tetrahydro-pyran-3,4,5-triol.In one aspect, the crystalline form is non-ionic. In another aspect, thecrystalline form has differential scanning calorimetry endotherms atabout 156° C. and/or about 158° C. In another aspect, the crystallineform has a molar ratio of L-proline to(2R,3S,4R,5R,6S)-2-Hydroxymethyl-6-[4-isopropyl-3-(1,2,3,4-tetrahydro-quinolin-7-ylmethyl)-phenyl]-tetrahydro-pyran-3,4,5-triolof 1:1. In one aspect, the crystalline form has powder X-raydiffractions peaks substantially the same as those listed in Table 4.

In one embodiment, the invention provides a crystalline form ofL-proline co-crystal of(2S,3R,4R,5S,6R)-2-[3-(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol.In one aspect, the crystalline form has a molar ratio of L-proline to(2S,3R,4R,5S,6R)-2-[3-(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triolof 2:1. In another aspect, the crystalline form is non-ionic. In anotheraspect, the crystalline form has a differential scanning calorimetryendotherm at about 176° C. In another aspect, the crystalline form haspowder X-ray diffraction peak(s) at about 6.1, 9.1, 12.8, 15.2, 16.5,17.8, 18.9, 20.9, and/or 28.4. In another aspect, the crystalline formhas powder X-ray diffraction pattern which is substantially the same asthe powder X-ray diffraction pattern shown in FIG. 4.

In the preceding paragraphs defining the molar ratio for a crystallineforms of L-proline and a compound of the invention, the phrase “a molarratio of about 1:1” is used to indicate that the crystalline form hasbetween 0.9-1.1 moles of a compound of the invention to 1 mole ofL-proline. Likewise, the phrase “a molar ratio of about 1:2” is used toindicate that the crystalline form has between 0.9-1.1 moles of acompound of the invention to 2 moles of L-proline.

When it is stated herein that the present invention relates to acrystalline form of an L-proline co-crystal of a compound of theinvention such as,(2S,3R,4R,5S,6R)-2-[4-Chloro-3-(3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol,(2S,3R,4R,5S,6R)-2-[4-Cyclopropyl-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol,(2S,3R,4R,5S,6R)-2-[3-(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol,or(2R,3S,4R,5R,6S)-2-Hydroxymethyl-6-[4-isopropyl-3-(1,2,3,4-tetrahydro-quinolin-7-ylmethyl)-phenyl]-tetrahydro-pyran-3,4,5-triol,the degree of crystallinity as determined by X-ray powder diffractiondata is conveniently greater than about 60%, more conveniently greaterthan about 80%, preferably greater than about 90%.

In the preceding paragraphs defining the X-ray powder diffraction peaksfor a crystalline forms of L-proline and a compound of the invention,the term “at about” is used to indicate that the precise position ofpeaks (i.e. the recited 2-theta angle values) should not be construed asbeing absolute values because, as will be appreciated by those skilledin the art, the precise position of the peaks may vary slightly betweenone machine and another, from one sample to another, or as a result ofslight variations in measurement conditions utilized. It is also statedin the preceding paragraphs that a crystalline form of a 1:1 L-prolineco-crystal of(2S,3R,4R,5S,6R)-2-[4-Chloro-3-(3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol,a 1:1 L-proline co-crystal of(2S,3R,4R,5S,6R)-2-[4-Cyclopropyl-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol,a 1:1 L-proline co-crystal of(2S,3R,4R,5S,6R)-2-[3-(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol,a 1:1 L-proline co-crystal of(2R,3S,4R,5R,6S)-2-Hydroxymethyl-6-[4-isopropyl-3-(1,2,3,4-tetrahydro-quinolin-7-ylmethyl)-phenyl]-tetrahydro-pyran-3,4,5-triol,and a 2:1 L-proline co-crystal of(2S,3R,4R,5S,6R)-2-[3-(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triolhave powder X-ray diffraction patterns that have substantially the samemost prominent peaks (2-theta angle values) shown in Tables 1A, 2A, 3A,4, and 5, respectively; and that an L-proline co-crystal of(2S,3R,4R,5S,6R)-2-[3-(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triolwhich has about a 1:1 molar ratio has substantially the same powderX-ray diffraction spectrum as shown in FIG. 2 and that an L-prolineco-crystal of(2S,3R,4R,5S,6R)-2-[3-(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triolwhich has about a 2:1 molar ratio has substantially the same powderX-ray diffraction spectrum as shown in FIG. 4. It shall be appreciatedthat the use of the term ‘substantially’ in this context is alsointended to indicate that the 2-theta angle values of the powder X-raydiffraction patterns may vary slightly from one machine to another, fromone sample to another, or as a result of slight variations inmeasurement conditions utilized, so the peak positions shown in theTable or in the specta are again not to be construed as absolute values.

In this regard, it is known in the art that a powder X-ray diffractionpattern may be obtained which has one or more measurement errorsdepending on measurement conditions (such as equipment, samplepreparation or machine used). In particular, it is generally known thatintensities in an X-ray powder diffraction pattern may fluctuatedepending on measurement conditions and sample preparation. For example,persons skilled in the art of powder X-ray diffraction will realize thatthe relative intensity of peaks can be affected by, for example, grainsabove 30 microns in size and non-unitary aspect ratios, which may affectanalysis of samples. The skilled person will also realize that theposition of reflections can be affected by the precise height at whichthe sample sits in the diffractometer and the zero calibration of thediffractometer. The surface planarity of the sample may also have asmall effect. Hence a person skilled in the art will appreciate that thediffraction pattern data presented herein is not to be construed asabsolute (for further information see Jenkins, R & Snyder, R. L.‘Introduction to X-Ray Powder Diffractometry’ John Wiley & Sons, 1996).Therefore, it shall be understood that the crystalline form of the 1:1L-proline co-crystal of(2S,3R,4R,5S,6R)-2-[4-Chloro-3-(3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol,the 1:1 L-proline co-crystal of(2S,3R,4R,5S,6R)-2-[4-Cyclopropyl-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol,the 1:1 L-proline co-crystal of(2S,3R,4R,5S,6R)-2-[3-(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol,the 1:1 L-proline co-crystal of(2R,3S,4R,5R,6S)-2-Hydroxymethyl-6-[4-isopropyl-3-(1,2,3,4-tetrahydro-quinolin-7-ylmethyl)-phenyl]-tetrahydro-pyran-3,4,5-triol,and the 2:1 L-proline co-crystal of(2S,3R,4R,5S,6R)-2-[3-(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triolof the present invention is not limited to the crystals that providepowder X-ray diffraction patterns having identical peaks as shown inTables 1A, 2A, 3A, 4, and 5, respectively, and any crystals providingX-ray powder diffraction patterns substantially the same as that shownin Table 1A, 2A, 3A, 4, and 5, respectively, fall within the scope ofthe present invention. Likewise, it shall be understood that thecrystalline form of an L-proline co-crystal of(2S,3R,4R,5S,6R)-2-[3-(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triolof the present invention is not limited to the crystals that providepowder X-ray diffraction spectra having identical peaks as shown in FIG.2 or 4, respectively, and any crystals providing X-ray powderdiffraction spectra substantially the same as that shown in FIG. 2 or 4,fall within the scope of the present invention. A person skilled in theart of powder X-ray diffraction is able to judge the substantialidentity of powder X-ray diffraction spectra.

Generally, a measurement error of a diffraction angle in a powder X-raydiffractogram is about 20=0.5 degrees or less (or, more suitably, about20=0.2 degrees or less) and such degree of a measurement error should betaken into account when interpreting the peak positions referred to thetext above and in Tables 1, 1A, 2, 2A, 3, 3A, 4, and 4A and in thespectra shown in FIGS. 2 and 4. Therefore, where it is stated, forexample, that the co-crystal has an X-ray powder diffraction patternwith a peak at about 20=17.3 degree (or any one of the other anglesmentioned above) then this can be interpreted as being 20=17.3 degreeplus or minus 0.5 degree, or 20=17.3 degree plus or minus 0.2 degree.

Isomeric Forms

Compounds of the invention may exist in one or more geometrical,optical, enantiomeric, diastereomeric and tautomeric forms, includingbut not limited to cis- and trans-forms, E- and Z-forms, R-, S- andmeso-forms, keto-, and enol-forms. All such isomeric forms are includedwithin the invention. The isomeric forms may be in isomerically pure orenriched form, as well as in mixtures of isomers (e.g. racemic ordiastereomeric mixtures).

Accordingly, the invention provides:

-   -   stereoisomeric mixtures of compounds of Formula (I);    -   a diastereomerically enriched or diastereomerically pure isomer        of a compound of Formula (I); or    -   an enantiomerically enriched or enantiomerically pure isomer of        a compound of Formula (I).

Where appropriate isomers can be separated from their mixtures by theapplication or adaptation of known methods (e.g. chromatographictechniques and recrystallisation techniques). Where appropriate isomerscan be prepared by the application or adaptation of known methods (e.g.asymmetric synthesis).

Unless otherwise indicated, the present invention is meant to includeall such possible isomers, as well as their racemic and optically pureforms. Optically active (+) and (−), (R)- and (S)-, or (D)- and(L)-isomers may be prepared using chiral synthons or chiral reagents, orresolved using conventional techniques, such as HPLC using a chiralcolumn. When the compounds described herein contain olefinic doublebonds or other centers of geometric asymmetry, and unless specifiedotherwise, it is intended that the compounds include both E and Zgeometric isomers. Likewise, all tautomeric forms are also intended tobe included.

A “stereoisomer” refers to a compound made up of the same atoms bondedby the same bonds but having different three-dimensional structures,which are not interchangeable. The present invention contemplatesvarious stereoisomers and mixtures thereof and includes “enantiomers”,which refers to two stereoisomers whose molecules arenon-superimposeable mirror images of one another.

Isotopic Labeling

The invention includes pharmaceutically acceptable isotopically-labelledcompounds of Formula (I) wherein one or more atoms are replaced by atomshaving the same atomic number, but an atomic mass or mass numberdifferent from the atomic mass or mass number usually found in nature.

Examples of isotopes suitable for inclusion in the compounds of theinvention include isotopes of hydrogen, such as ²H and ³H, carbon, suchas ¹¹C, ¹³C and ¹⁴C, chlorine, such as ³⁶Cl, fluorine, such as ¹⁸F,iodine, such as ¹²³I and ¹²⁵I, nitrogen, such as ¹³N and ¹⁵N, oxygen,such as ¹⁵O, ¹⁷O and ¹⁸O, phosphorus, such as ³²P, and sulphur, such as³⁵S. Certain isotopically-labelled compounds of Formula (I), forexample, those incorporating a radioactive isotope, are useful in drugand/or substrate tissue distribution studies. The radioactive isotopes³H and ¹⁴C are particularly useful for this purpose in view of theirease of incorporation and ready means of detection.

Substitution with positron emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O and¹³N, can be useful in Positron Emission Topography (PET) studies forexamining substrate receptor occupancy.

Isotopically-labelled compounds of Formula (I) can generally be preparedby conventional techniques known to those skilled in the art or byprocesses analogous to those described herein using an appropriateisotopically-labelled reagent in place of the non-labelled reagentpreviously employed.

Therapeutic Definitions

As used herein, “treatment” includes curative and prophylactictreatment. As used herein, a “patient” means an animal, preferably amammal, preferably a human, in need of treatment.

The amount of the compound of the invention administered should be atherapeutically effective amount where the compound or derivative isused for the treatment of a disease or condition and a prophylacticallyeffective amount where the compound or derivative is used for theprevention of a disease or condition.

The term “therapeutically effective amount” used herein refers to theamount of compound needed to treat or ameliorate a targeted disease orcondition. The term “prophylactically effective amount” used hereinrefers to the amount of compound needed to prevent a targeted disease orcondition. The exact dosage will generally be dependent on the patient'sstatus at the time of administration. Factors that may be taken intoconsideration when determining dosage include the severity of thedisease state in the patient, the general health of the patient, theage, weight, gender, diet, time, frequency and route of administration,drug combinations, reaction sensitivities and the patient's tolerance orresponse to therapy. The precise amount can be determined by routineexperimentation, but may ultimately lie with the judgement of theclinician. Generally, an effective dose will be from 0.01 mg/kg/day(mass of drug compared to mass of patient) to 1000 mg/kg/day, e.g. 1mg/kg/day to 100 mg/kg/day or 1 mg/kg/day to 10 mg/kg/day. Compositionsmay be administered individually to a patient or may be administered incombination with other agents, drugs or hormones.

As used herein, the terms “disease” and “condition” may be usedinterchangeably or may be different in that the particular malady orcondition may not have a known causative agent (so that etiology has notyet been worked out) and it is therefore not yet recognized as a diseasebut only as an undesirable condition or syndrome, wherein a more or lessspecific set of symptoms have been identified by clinicians. As usedherein, the term “disorder” is synonymous with “condition”.

Treatment of Diseases and Conditions

Compounds of Formula (I) have been found to be inhibitors of SGLT. Asused herein, inhibition of SGLT means inhibition exclusively of SGLT2,inhibition exclusively of SGLT1 or inhibition of both SGLT1 and SGLT2.

The invention provides a compound of Formula (I) for use in therapy. Theinvention further provides a pharmaceutical composition comprising acompound of Formula (I) in combination with a pharmaceuticallyacceptable excipient.

The invention further provides a method for the treatment of a diseaseor condition mediated by the sodium D-glucose co-transporter, comprisingthe step of administering a therapeutically effective amount of acompound of Formula (I) to a patient. The invention also provides theuse of a compound of Formula (I) in the manufacture of a medicament forthe treatment of a disease or condition mediated by the sodium D-glucoseco-transporter. The invention also provides a compound of Formula (I)for use in treating a disease or condition mediated by the sodiumD-glucose co-transporter.

The SGLT inhibitory activity of the compounds of the invention may bedemonstrated by the SGLT2 and SGLT1 assays disclosed hereinbelow.Preferred compounds of the invention have an IC₅₀ in the SGLT2 assay of<100 nM, in one embodiment <30 nM, in one embodiment <20 nM, in oneembodiment <10 nM, in another embodiment <5 nM, and in anotherembodiment <1 nM, and in another embodiment <0.5 nM. In anotherembodiment, preferred compounds of the invention have an IC₅₀ in theSGLT1 assay of <10,000 nM, in one embodiment <1500 nM, in one embodiment<1000 nM, in one embodiment <700 nM, in another embodiment <500 nM andin another embodiment <200 nM.

The present invention also provides a method of treating diabetescomprising administering a compound of Formula (I) to a subject in needthereof.

In another embodiment, the invention provides a method of treating adisease or condition mediated by the sodium D-glucose co-transporter ina mammal, comprising administering to the mammal in need thereof atherapeutically effective amount of a compound according to any one ofclaims 1 to 36.

The compounds of the present invention are useful as both prophylacticand therapeutic treatments for diseases or conditions related to theinhibition of SGLT-2 and SGLT-1.

Diseases and Conditions Mediated by the Sodium D-Glucose Co-Transporter

The invention is useful for the treatment of a disease or disordermediated by the sodium D-glucose co-transporter. Diseases and conditionsmediated by the sodium D-glucose co-transporter include: metabolicdisorders, retinopathy, nephropathy, diabetic foot, ulcers,macroangiopathies, metabolic acidosis or ketosis, reactivehypoglycaemia, hyperinsulinaemia, glucose metabolic disorder, insulinresistance, metabolic syndrome (such as dyslipidemia, obesity, insulinresistance, hypertension, microalbuminemia, hyperuricaemia, andhypercoagulability), dyslipidaemias of different origins,atherosclerosis and related diseases, high blood pressure, chronic heartfailure, edema, hyperuricaemia, Syndrome X, diabetes, insulinresistance, decreased glucose tolerance (also known as impaired glucosetolerance, IGT), non-insulin-dependent diabetes mellitus, Type IIdiabetes, Type I diabetes, diabetic complications, body weightdisorders, weight loss, body mass index and leptin related diseases. Inone embodiment, the diseases and conditions include metabolic syndrome(such as dyslipidemia, obesity, insulin resistance, hypertension,microalbuminemia, hyperuricaemia, and hypercoagulability), Syndrome X,diabetes, insulin resistance, decreased glucose tolerance (also known asimpaired glucose tolerance, IGT), non-insulin-dependent diabetesmellitus, Type II diabetes, Type I diabetes, diabetic complications,body weight disorders, weight loss, body mass index and leptin relateddiseases. In one embodiment, the disease or disorder is decreasedglucose tolerance, Type II diabetes or obesity.

Compounds of formula (I) may be also suitable for preventing beta-celldegeneration such as apoptosis or necrosis of pancreatic beta cells, forimproving or restoring the functionality of pancreatic cells, increasingthe number and size of pancreatic beta cells, for use as diuretics orantihypertensives and for the prevention and treatment of acute renalfailure.

As a further aspect, the invention relates to a method for treating adisorder selected from type I and type II diabetes mellitus,complications of diabetes, comprising administration of an effectiveamount of a compound of formula (I) or a pharmaceutically acceptablesalt thereof.

As used herein a patient is suffering from “obesity” if the patientexhibits at least one of:

-   -   a body mass index (BMI), i.e. the patient's mass (in kg) divided        by the square of the patient's height (in m), of 30 or more;    -   an absolute waist circumference of >102 cm in men or >88 cm in        women;    -   a waist-to-hip ratio >0.9 in men or >0.85 in women; or    -   a percent body fat >25% in men or >30% in women.

As used herein a patient is suffering from “Type II diabetes” if theymeet the World Health Organisation criteria for Diabetes diagnosis(Definition and diagnosis of diabetes mellitus and intermediatehyperglycaemia, WHO, 2006), i.e. the patient exhibits at least one of:

-   -   a fasting plasma glucose ≧7.0 mmol/l (126 mg/dl); or    -   a venous plasma glucose ≧11.1 mmol/l (200 mg/dl) 2 hours after        ingestion of 75 g oral glucose load.

As used herein a patient is suffering from “IGT” if they meet the WorldHealth Organisation criteria for IGT diagnosis (Definition and diagnosisof diabetes mellitus and intermediate hyperglycaemia, WHO, 2006), i.e.the patient exhibits both of:

-   -   a fasting plasma glucose <7.0 mmol/l (126 mg/dl); and    -   a venous plasma glucose ≧7.8 and <11.1 mmol/l (200 mg/dl) 2        hours after ingestion of 75 g oral glucose load.

Administration & Formulation General

For pharmaceutical use, the compounds of the invention may beadministered as a medicament by enteral or parenteral routes, includingintravenous, intramuscular, subcutaneous, transdermal, airway (aerosol),oral, intranasal, rectal, vaginal and topical (including buccal andsublingual) administration. The compounds of Formula (I) should beassessed for their biopharmaceutical properties, such as solubility andsolution stability (across pH), permeability, etc., in order to selectthe most appropriate dosage form and route of administration fortreatment of the proposed indication.

The compounds of the invention may be administered as crystalline oramorphous products. The compounds of the invention may be administeredalone or in combination with one or more other compounds of theinvention or in combination with one or more other drugs (or as anycombination thereof). Generally, they will be administered as aformulation in association with one or more pharmaceutically acceptableexcipients. The term “excipient” includes any ingredient other than thecompound(s) of the invention which may impart either a functional (e.gdrug release rate controlling) and/or a non-functional (e.g. processingaid or diluent) characteristic to the formulations. The choice ofexcipient will to a large extent depend on factors such as theparticular mode of administration, the effect of the excipient onsolubility and stability, and the nature of the dosage form.

The present invention provides a pharmaceutical composition comprising acompound according to Formula (I) and a pharmaceutically acceptableexcipient.

Typical pharmaceutically acceptable excipients include:

-   -   diluents, e.g. lactose, dextrose, sucrose, mannitol, sorbitol,        cellulose and/or glycine;    -   lubricants, e.g. silica, talcum, stearic acid, its magnesium or        calcium salt and/or polyethyleneglycol;    -   binders, e.g. magnesium aluminum silicate, starch paste,        gelatin, tragacanth, methylcellulose, sodium        carboxymethylcellulose and/or polyvinylpyrrolidone;    -   disintegrants, e.g. starches, agar, alginic acid or its sodium        salt, or effervescent mixtures; and/or    -   absorbants, colorants, flavors and/or sweeteners.

A thorough discussion of pharmaceutically acceptable excipients isavailable in Gennaro, Remington: The Science and Practice of Pharmacy2000, 20th edition (ISBN: 0683306472).

Accordingly, in one embodiment, the present invention provides apharmaceutical composition comprising a compound of Formula (I) and apharmaceutically acceptable excipient.

Oral Administration

The compounds of the invention may be administered orally. Oraladministration may involve swallowing, so that the compound enters thegastrointestinal tract, and/or buccal, lingual, or sublingualadministration by which the compound enters the blood stream directlyfrom the mouth.

Formulations suitable for oral administration include solid plugs, solidmicroparticulates, semi-solid and liquid (including multiple phases ordispersed systems) such as tablets; soft or hard capsules containingmulti- or nano-particulates, liquids (e.g. aqueous solutions), emulsionsor powders; lozenges (including liquid-filled); chews; gels; fastdispersing dosage forms; films; ovules; sprays; and buccal/mucoadhesivepatches.

Formulations suitable for oral administration may also be designed todeliver the compounds of Formula (I) in an immediate release manner orin a rate-sustaining manner, wherein the release profile can be delayed,pulsed, controlled, sustained, or delayed and sustained or modified insuch a manner which optimises the therapeutic efficacy of the saidcompounds. Means to deliver compounds in a rate-sustaining manner areknown in the art and include slow release polymers that can beformulated with the said compounds to control their release.

Examples of rate-sustaining polymers include degradable andnon-degradable polymers that can be used to release the said compoundsby diffusion or a combination of diffusion and polymer erosion. Examplesof rate-sustaining polymers include hydroxypropyl methylcellulose,hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, sodiumcarboxymethyl cellulose, polyvinyl alcohol, polyvinyl pyrrolidone,xanthum gum, polymethacrylates, polyethylene oxide and polyethyleneglycol.

Liquid (including multiple phases and dispersed systems) formulationsinclude emulsions, suspensions, solutions, syrups and elixirs. Suchformulations may be presented as fillers in soft or hard capsules (made,for example, from gelatin or hydroxypropylmethylcellulose) and typicallycomprise a carrier, for example, water, ethanol, polyethylene glycol,propylene glycol, methylcellulose, or a suitable oil, and one or moreemulsifying agents and/or suspending agents. Liquid formulations mayalso be prepared by the reconstitution of a solid, for example, from asachet.

The compounds of the invention may also be used in fast-dissolving,fast-disintegrating dosage forms such as those described in Liang andChen, Expert Opinion in Therapeutic Patents 2001, 11(6): 981-986.

The formulation of tablets is discussed in H. Lieberman and L. Lachman,Pharmaceutical Dosage Forms: Tablets 1980, vol. 1 (Marcel Dekker, NewYork).

Parenteral Administration

The compounds of the invention can be administered parenterally.

The compounds of the invention may be administered directly into theblood stream, into subcutaneous tissue, into muscle, or into an internalorgan. Suitable means for administration include intravenous,intraarterial, intrathecal, intraventricular, intraurethral,intrasternal, intracranial, intramuscular, intrasynovial andsubcutaneous. Suitable devices for administration include needle(including microneedle) injectors, needle-free injectors and infusiontechniques.

Parenteral formulations are typically aqueous or oily solutions. Wherethe solution is aqueous, excipients such as sugars (including butrestricted to glucose, mannitol, sorbitol, etc.) salts, carbohydratesand buffering agents (preferably to a pH of from 3 to 9), but, for someapplications, they may be more suitably formulated as a sterilenon-aqueous solution or as a dried form to be used in conjunction with asuitable vehicle such as sterile, pyrogen-free water (WFI).

Parenteral formulations may include implants derived from degradablepolymers such as polyesters (i.e. polylactic acid, polylactide,polylactide-co-glycolide, polycapro-lactone, polyhydroxybutyrate),polyorthoesters and polyanhydrides. These formulations may beadministered via surgical incision into the subcutaneous tissue,muscular tissue or directly into specific organs.

The preparation of parenteral formulations under sterile conditions, forexample, by lyophilisation, may readily be accomplished using standardpharmaceutical techniques well known to those skilled in the art.

The solubility of compounds of Formula (I) used in the preparation ofparenteral solutions may be increased by the use of appropriateformulation techniques, such as the incorporation of co-solvents and/orsolubility-enhancing agents such as surfactants, micelle structures andcyclodextrins.

Inhalation & Intranasal Administration

The compounds of the invention can be administered intranasally or byinhalation, typically in the form of a dry powder (either alone, as amixture, for example, in a dry blend with lactose, or as a mixedcomponent particle, for example, mixed with phospholipids, such asphosphatidylcholine) from a dry powder inhaler, as an aerosol spray froma pressurised container, pump, spray, atomiser (preferably an atomiserusing electrohydrodynamics to produce a fine mist), or nebuliser, withor without the use of a suitable propellant, such as1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane, or asnasal drops. For intranasal use, the powder may comprise a bioadhesiveagent, for example, chitosan or cyclodextrin.

The pressurised container, pump, spray, atomizer, or nebuliser containsa solution or suspension of the compound(s) of the invention comprising,for example, ethanol, aqueous ethanol, or a suitable alternative agentfor dispersing, solubilising, or extending release of the active, apropellant(s) as solvent and an optional surfactant, such as sorbitantrioleate, oleic acid, or an oligolactic acid.

Prior to use in a dry powder or suspension formulation, the drug productis micronised to a size suitable for delivery by inhalation (typicallyless than 5 microns). This may be achieved by any appropriatecomminuting method, such as spiral jet milling, fluid bed jet milling,supercritical fluid processing to form nanoparticles, high pressurehomogenisation, or spray drying.

Capsules (made, for example, from gelatin orhydroxypropylmethylcellulose), blisters and cartridges for use in aninhaler or insufflator may be formulated to contain a powder mix of thecompound of the invention, a suitable powder base such as lactose orstarch and a performance modifier such as l-leucine, mannitol, ormagnesium stearate. The lactose may be anhydrous or in the form of themonohydrate, preferably the latter. Other suitable excipients includedextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose andtrehalose.

Formulations for inhaled/intranasal administration may be formulated tobe immediate and/or modified release using, for example, PGLA. Modifiedrelease formulations include delayed-, sustained-, pulsed-, controlled-,targeted and programmed release.

Transdermal Administration

Suitable formulations for transdermal application include atherapeutically effective amount of a compound of the invention withcarrier. Advantageous carriers include absorbable pharmacologicallyacceptable solvents to assist passage through the skin of the host.Characteristically, transdermal devices are in the form of a bandagecomprising a backing member, a reservoir containing the compoundoptionally with carriers, optionally a rate controlling barrier todeliver the compound of the skin of the host at a controlled andpredetermined rate over a prolonged period of time, and means to securethe device to the skin.

Combination Therapy

A compound of formula (I) of the present invention may be usefullycombined with another pharmacologically active compound, or with two ormore other pharmacologically active compounds, for use in therapy. Forexample, a compound of the formula (I), or a pharmaceutically acceptablesalt thereof, as defined above, may be administered simultaneously,sequentially or separately in combination with one or more agents forthe treatment of disorders previously listed.

Therapeutic agents which are suitable for such a combination include,for example, antidiabetic agents such as metformin, sulphonylureas (e.g.glibenclamide, tolbutamide, glimepiride), nateglinide, repaglinide,thiazolidinediones (e.g. rosiglitazone, pioglitazone),PPAR-gamma-agonists (e.g. GI 262570) and antagonists, PPAR-gamma/alphamodulators (e.g. KRP 297), alpha-glucosidase inhibitors (e.g. acarbose,voglibose), DPPIV inhibitors (e.g. LAF237, MK-431), alpha2-antagonists,insulin and insulin analogues, GLP-1 and GLP-1 analogues (e.g.exendin-4) or amylin. The list also includes inhibitors of proteintyrosinephosphatase 1, substances that affect deregulated glucoseproduction in the liver, such as e.g. inhibitors ofglucose-6-phosphatase, orfructose-1,6-bisphosphatase, glycogenphosphorylase, glucagon receptor antagonists and inhibitors ofphosphoenol pyruvate carboxykinase, glycogen synthase kinase or pyruvatedehydrokinase, lipid lowering agents such as for exampleHMG-CoA-reductase inhibitors (e.g. simvastatin, atorvastatin), fibrates(e.g. bezafibrate, fenofibrate), nicotinic acid and the derivativesthereof, PPAR-alpha agonists, PPAR-delta agonists, ACAT inhibitors (e.g.avasimibe) or cholesterol absorption inhibitors such as, for example,ezetimibe, bile acid-binding substances such as, for example,cholestyramine, inhibitors of ileac bile acid transport, HDL-raisingcompounds such as CETP inhibitors or ABC1 regulators or activesubstances for treating obesity, such as sibutramine ortetrahydrolipostatin, dexfenfluramine, axokine, antagonists of thecannabinoidi receptor, MCH-1 receptor antagonists, MC4 receptoragonists, NPY5 or NPY2 antagonists or β3-agonists such as SB-418790 orAD-9677 and agonists of the 5HT2c receptor.

Moreover, combinations with drugs for influencing high blood pressure,chronic heart failure or atherosclerosis such as e.g. A-II antagonistsor ACE inhibitors, ECE inhibitors, diuretics, β-blockers,Ca-antagonists, centrally acting antihypertensives, antagonists of thealpha-2-adrenergic receptor, inhibitors of neutral endopeptidase,thrombocyte aggregation inhibitors and others or combinations thereofare suitable. Examples of angiotensin II receptor antagonists arecandesartan cilexetil, potassium losartan, eprosartan mesylate,valsartan, telmisartan, irbesartan, EXP-3174, L-158809, EXP-3312,olmesartan, medoxomil, tasosartan, KT-3-671, GA-01 13, RU-64276,EMD-90423, BR-9701, etc. Angiotensin II receptor antagonists arepreferably used for the treatment or prevention of high blood pressureand complications of diabetes, often combined with a diuretic such ashydrochlorothiazide.

A combination with uric acid synthesis inhibitors or uricosurics issuitable for the treatment or prevention of gout.

A combination with GABA-receptor antagonists, Na-channel blockers,topiramat, protein-kinase C inhibitors, advanced glycation end productinhibitors or aldose reductase inhibitors may be used for the treatmentor prevention of complications of diabetes.

Such combinations may offer significant advantages, includingsynergistic activity, in therapy.

The present invention thus provides:

-   -   The use of an agent selected from the group consisting of        insulin, insulin derivative or mimetic; insulin secretagogue;        insulinotropic sulfonylurea receptor ligand; PPAR ligand;        insulin sensitizer; biguanide; alpha-glucosidase inhibitors;        GLP-1, GLP-1 analog or mimetic; DPPIV inhibitor; HMG-CoA        reductase inhibitor; squalene synthase inhibitor; FXR or LXR        ligand; cholestyramine; fibrates; nicotinic acid, and aspirin in        the manufacture of a medicament for the treatment of a disease        or condition in a subject mediated by the sodium D-glucose        co-transporter, wherein the agent is administered in combination        with a compound according to Formula (I);    -   The use of a compound according to Formula (I) in the        manufacture of a medicament for the treatment of a disease or        condition in a subject mediated by the sodium D-glucose        co-transporter, wherein the compound is administered in        combination with an agent selected from the group consisting of        insulin, insulin derivative or mimetic; insulin secretagogue;        insulinotropic sulfonylurea receptor ligand; PPAR ligand;        insulin sensitizer; biguanide; alpha-glucosidase inhibitors;        GLP-1, GLP-1 analog or mimetic; DPPIV inhibitor; HMG-CoA        reductase inhibitor; squalene synthase inhibitor; FXR or LXR        ligand; cholestyramine; fibrates; nicotinic acid, and aspirin,        and    -   The use of a compound according to any one of claims 1 to 36 in        combination with an agent selected from the group consisting of        insulin, insulin derivative or mimetic; insulin secretagogue;        insulinotropic sulfonylurea receptor ligand; PPAR ligand;        insulin sensitizer; biguanide; alpha-glucosidase inhibitors;        GLP-1, GLP-1 analog or mimetic; DPPIV inhibitor; HMG-CoA        reductase inhibitor; squalene synthase inhibitor; FXR or LXR        ligand; cholestyramine; fibrates; nicotinic acid, and aspirin in        the manufacture of a medicament for treating a disease or        condition in a subject mediated by the sodium D-glucose        co-transporter,    -   Wherein the diseases or conditions may be as described herein.

The present invention also provides a pharmaceutical compositioncomprising a therapeutically effective amount of a compound of Formula(I) in combination with a therapeutically effective amount of insulin,insulin derivative or mimetic; insulin secretagogue; insulinotropicsulfonylurea receptor ligand; PPAR ligand; insulin sensitizer;biguanide; alpha-glucosidase inhibitors; GLP-1, GLP-1 analog or mimetic;DPPIV inhibitor; HMG-CoA reductase inhibitor; squalene synthaseinhibitor; FXR or LXR ligand; cholestyramine; fibrates; nicotinic acid;or aspirin. In another embodiment, the invention provides a productcomprising a compound of Formula (I) and an agent selected from thegroup consisting of insulin, insulin derivative or mimetic; insulinsecretagogue; insulinotropic sulfonylurea receptor ligand; PPAR ligand;insulin sensitizer; biguanide; alpha-glucosidase inhibitors; GLP-1,GLP-1 analog or mimetic; DPPIV inhibitor; HMG-CoA reductase inhibitor;squalene synthase inhibitor; FXR or LXR ligand; cholestyramine;fibrates; nicotinic acid, and aspirin for simultaneous, separate orsequential use in therapy.

Chemical Definitions

As used herein, the term “alkyl” refers to a fully saturated branched orunbranched hydrocarbon moiety. Preferably the alkyl comprises 1 to 20carbon atoms, more preferably 1 to 16 carbon atoms, 1 to 10 carbonatoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms. Representativeexamples of alkyl include, but are not limited to, methyl, ethyl,n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl,n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl,2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, orn-decyl.

“Alkylene” refers to a straight or branched divalent hydrocarbon chainconsisting solely of carbon and hydrogen atoms, having from one totwelve carbon atoms, preferably one to 6 carbon atoms, and linking therest of the molecule to a radical group. Examples of alkylene groupsinclude methylene, ethylene, propylene, n-butylene, and the like. Thealkylene is attached to the rest of the molecule through a single bondand to the radical group through a single bond. The points of attachmentof the alkylene to the rest of the molecule and to the radical group canbe through one carbon or any two carbons within the chain.

“Halogen” or “halo” may be fluoro, chloro, bromo or iodo.

The term “alkenyl” refers to a monovalent hydrocarbon having at leastone carbon-carbon double bond. The term “C₂-C₆alkenyl” refers to amonovalent hydrocarbon having two to six carbon atoms and comprising atleast one carbon-carbon double bond.

The term “alkynyl” refers to a monovalent hydrocarbon having at leastone carbon-carbon triple bond. The term “C₂-C₆-alkynyl” refers to amonovalent hydrocarbon having two to six carbon atoms and comprising atleast one carbon-carbon triple bond.

As used herein, the term “alkoxy” refers to alkyl-O—, wherein alkyl isdefined herein above. Representative examples of alkoxy include, but arenot limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy,tert-butoxy, pentyloxy, hexyloxy, cyclopropyloxy-, cyclohexyloxy- andthe like. Preferably, alkoxy groups have about 1-6, more preferablyabout 1-4 carbons.

Alkyl, alkenyl, alkynyl, and alkoxy groups, containing the requisitenumber of carbon atoms, can be unbranched or branched. The requisitenumber of carbon may be represented as C₁₋₆, C₁₋₄, etc.

The term “aryl” refers to monocyclic or bicyclic aromatic hydrocarbongroups having 6-carbon atoms in the ring portion. Non-limiting examplesinclude phenyl and naphthyl.

The term “aryl” also refers to a group in which a aryl ring is fused toone or more cycloalkyl or heterocyclyl rings, where the radical or pointof attachment is on the aryl ring. Nonlimiting examples include2,3-dihydro-1H-indene, 1,2,3,4-tetrahydronaphthyl and3,4-dihydro-2H-benzo[b][1,4]oxazinyl.

The term “arylalkyl” refers to an aryl group which is linked to anothermoiety via an alkyl group which may be branched or unbranched. Examplesof arylalkyl groups include benzyl, 2-phenyl-ethyl,2-(naphth-2-yl)-butan-1-yl, and the like.

The term “aryloxy” refers to an aryl group which is linked to anothermoiety through an oxygen atom, such as phenoxy.

As used herein, the term “heterocyclyl” refers to an optionallysubstituted, saturated or unsaturated non-aromatic ring or ring system,e.g., which is a 4-, 5-, 6-, or 7-membered monocyclic, 7-, 8-, 9-, 10-,11-, or 12-membered bicyclic or 10-, 11-, 12-, 13-, 14- or 15-memberedtricyclic ring system and contains at least one heteroatom selected fromO, S and N, where the N and S can also optionally be oxidized to variousoxidation states. The heterocyclic group can be attached at a heteroatomor a carbon atom. The heterocyclyl can include fused or bridged rings aswell as spirocyclic rings. Examples of heterocycles includedihydrofuranyl, [1,3]dioxolane, 1,4-dioxane, 1,4-dithiane, piperazinyl,1,3-dioxolane, imidazolidinyl, imidazolinyl, pyrrolidine, dihydropyran,oxathiolane, dithiolane, 1,3-dioxane, 1,3-dithianyl, oxathianyl,thiomorpholinyl, oxiranyl, aziridinyl, oxetanyl, azetidinyl,tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl,morpholinyl, piperazinyl, azepinyl, oxapinyl, oxazepinyl and diazepinyl.

As used herein, the term “cycloalkyl” refers to saturated or partiallyunsaturated (but not aromatic) monocyclic, bicyclic or tricyclichydrocarbon groups of 3-12 carbon atoms, preferably 3-9, or 3-7 carbonatoms, Exemplary monocyclic hydrocarbon groups include, but are notlimited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl,cyclohexyl or cyclohexenyl. Exemplary bicyclic hydrocarbon groupsinclude bornyl, decahydronaphthyl, bicyclo[2.1.1]hexyl,bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl,6,6-dimethylbicyclo[3.1.1]heptyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl,or bicyclo[2.2.2]octyl. Exemplary tricyclic hydrocarbon groups includeadamantyl.

The term “heterocycloxy” refers to a heterocyclyl which is linked toanother moiety through an oxygen atom, e.g. piperazin-2-yloxy.

As used herein, the term “heteroaryl” refers to a 5-14 memberedmonocyclic- or bicyclic- or polycyclic-aromatic ring system having 1 to8 heteroatoms selected from N, O or S. Preferably, the heteroaryl is a5-10 or 5-7 membered ring system. Examples of monocyclic heteroarylgroups include pyridyl, thienyl, furanyl, pyrrolyl, pyrazolyl,imidazoyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl,oxadiazolyl, thiadiazolyl and tetrazolyl. Examples of bicyclicheteroaryl groups include indolyl, benzofuranyl, quinolyl, isoquinolylindazolyl, indolinyl, isoindolyl, indolizinyl, benzamidazolyl, andquinolinyl.

The term “heteroaryl” also refers to a group in which a heteroaromaticring is fused to one or more cycloalkyl, or heterocyclyl rings, wherethe radical or point of attachment is on the heteroaromatic ring.Nonlimiting examples include 5,6,7,8-tetrahydroquinoline and6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidine.

A heteroaryl group may be mono-, bi-, tri-, or polycyclic, preferablymono-, bi-, or tricyclic, more preferably mono- or bicyclic.

The term “heteroarylalkyl” refers to an heteroaryl group which is linkedto another moiety via an alkyl group which may be branched orunbranched. Examples of heteroarylalkyl groups include2-(pyridin-3-yl)-ethyl, 3-(quinolin-7-yl)-butan-1-yl, and the like.

The term “heteroaryloxy” refers to a heteroaryl group which is linked toanother moiety through an oxygen atom, such as pyridin-3-lyoxy.

“Heteroaryl” and “heterocyclyl” is also intended to include oxidized Sor N, such as sulfinyl, sulfonyl and N-oxide of tertiary ring nitrogen.

Unless indicated explicitly otherwise, where combinations of groups arereferred to herein as one moiety, e.g. arylalkyl, the last mentionedgroup contains the atom by which the moiety is attached to the rest ofthe molecule.

An “amino” group as used herein refers to —NH₂. The term“N-(alkyl)amino” refers to an amino group in which one hydrogen isreplaced by an alkyl group. For example, N—(C₁₋₆alkyl)amino refers to anamino group in which one of the hydrogens has been replaced with analkyl group having from 1 to 6 carbon atoms. The term“N,N-di-(alkyl)amino” refers to an amino group in which both hydrogenshave been replaced by an alkyl group which may be the same or different.For example, N,N-di-(C₁₋₆alkyl)amino refers to an amino group in whichboth of the hydrogens have been replaced with an alkyl group which maybe the same or different having from 1 to 6 carbon atoms.

A “carbamoyl” group as used herein refers to —C(O)NH₂. The term“N-(alkyl)-carbamoyl” refers to a carbamoyl group in which one hydrogenis replaced by an alkyl group. For example, N—(C₁₋₆alkyl)-carbamoylrefers to a carbamoyl group in which one of the hydrogens has beenreplaced with an alkyl group having from 1 to 6 carbon atoms. The term“N,N-di-(alkyl)-carbamoyl” refers to a carbamoyl group in which bothhydrogens have been replaced by an alkyl group which may be the same ordifferent. For example, N,N-di-(C₁₋₆alkyl)-carbamoyl refers to acarbamoyl group in which both of the hydrogens have been replaced withan alkyl group which may be the same or different having from 1 to 6carbon atoms.

The term “alkanoyl” refers to a group having the formula —C(O)—R,wherein R is an alkyl group. For example, C₁₋₆alkanoyl refers to analkanoyl group which has from one to six carbon atoms, such as acetyl,isopropyl-carbonyl, and the like.

General

The term “comprising” encompasses “including” as well as “consisting”,e.g. a composition “comprising” X may consist exclusively of X or mayinclude something additional, e.g. X+Y.

The word “substantially” does not exclude “completely” e.g. acomposition which is “substantially free” from Y may be completely freefrom Y. Where necessary, the word “substantially” may be omitted fromthe definition of the invention.

The term “about” in relation to a numerical value x means, for example,x+10%.

Whenever appropriate, terms used in the singular will also include theplural and vice versa.

Unless it is explicitly stated that a group is substituted or mayoptionally be substituted, it is to be understood that the group isunsubstituted.

“Optional” or “optionally” means that the subsequently described eventof circumstances may or may not occur, and that the description includesinstances where said event or circumstance occurs and instances in whichit does not. For example, “optionally substituted aryl” means that thearyl radical may or may not be substituted and that the descriptionincludes both substituted aryl radicals and aryl radicals having nosubstitution.

Synthesis

Within the scope of this text, only a readily removable group that isnot a constituent of the particular desired end product of the compoundsof the present invention is designated a “protecting group”, unless thecontext indicates otherwise. The protection of functional groups by suchprotecting groups, the protecting groups themselves, and their cleavagereactions are described for example in standard reference works, such asJ. F. W. McOmie, “Protective Groups in Organic Chemistry”, Plenum Press,London and New York 1973.

Salts of compounds of the present invention having at least onesalt-forming group may be prepared in a manner known per se. Forexample, salts of compounds of the present invention having acid groupsmay be formed, for example, by treating the compounds with metalcompounds, such as alkali metal salts of suitable organic carboxylicacids, e.g. the sodium salt of 2-ethylhexanoic acid, with organic alkalimetal or alkaline earth metal compounds, such as the correspondinghydroxides, carbonates or hydrogen carbonates, such as sodium orpotassium hydroxide, carbonate or hydrogen carbonate, with correspondingcalcium compounds or with ammonia or a suitable organic amine,stoichiometric amounts or only a small excess of the salt-forming agentpreferably being used. Acid addition salts of compounds of the presentinvention are obtained in customary manner, e.g. by treating thecompounds with an acid or a suitable anion exchange reagent. Internalsalts of compounds of the present invention containing acid and basicsalt-forming groups, e.g. a free carboxy group and a free amino group,may be formed, e.g. by the neutralisation of salts, such as acidaddition salts, to the isoelectric point, e.g. with weak bases, or bytreatment with ion exchangers.

Salts can be converted in customary manner into the free compounds;metal and ammonium salts can be converted, for example, by treatmentwith suitable acids, and acid addition salts, for example, by treatmentwith a suitable basic agent.

Mixtures of isomers obtainable according to the invention can beseparated in a manner known per se into the individual isomers;diastereoisomers can be separated, for example, by partitioning betweenpolyphasic solvent mixtures, recrystallisation and/or chromatographicseparation, for example over silica gel or by e.g. medium pressureliquid chromatography over a reversed phase column, and racemates can beseparated, for example, by the formation of salts with optically puresalt-forming reagents and separation of the mixture of diastereoisomersso obtainable, for example by means of fractional crystallisation, or bychromatography over optically active column materials.

Intermediates and final products can be worked up and/or purifiedaccording to standard methods, e.g. using chromatographic methods,distribution methods, (re-) crystallization, and the like.

The following applies in general to all processes mentioned hereinbeforeand hereinafter.

All the above-mentioned process steps can be carried out under reactionconditions that are known per se, including those mentionedspecifically, in the absence or, customarily, in the presence ofsolvents or diluents, including, for example, solvents or diluents thatare inert towards the reagents used and dissolve them, in the absence orpresence of catalysts, condensation or neutralizing agents, for exampleion exchangers, such as cation exchangers, e.g. in the H+ form,depending on the nature of the reaction and/or of the reactants atreduced, normal or elevated temperature, for example in a temperaturerange of from about −100° C. to about 190° C., including, for example,from approximately −80° C. to approximately 150° C., for example at from−80 to −60° C., at room temperature, at from −20 to 40° C. or at refluxtemperature, under atmospheric pressure or in a closed vessel, whereappropriate under pressure, and/or in an inert atmosphere, for exampleunder an argon or nitrogen atmosphere.

At all stages of the reactions, mixtures of isomers that are formed canbe separated into the individual isomers, for example diastereoisomersor enantiomers, or into any desired mixtures of isomers, for exampleracemates or mixtures of diastereoisomers, for example analogously tothe methods described under “Additional process steps”.

The solvents from which those solvents that are suitable for anyparticular reaction may be selected include those mentioned specificallyor, for example, water, esters, such as lower alkyl-lower alkanoates,for example ethyl acetate, ethers, such as aliphatic ethers, for examplediethyl ether, or cyclic ethers, for example tetrahydrofuran or dioxane,liquid aromatic hydrocarbons, such as benzene or toluene, alcohols, suchas methanol, ethanol or 1- or 2-propanol, nitriles, such asacetonitrile, halogenated hydrocarbons, such as methylene chloride orchloroform, acid amides, such as dimethylformamide or dimethylacetamide, bases, such as heterocyclic nitrogen bases, for examplepyridine or N-methylpyrrolidin-2-one, carboxylic acid anhydrides, suchas lower alkanoic acid anhydrides, for example acetic anhydride, cyclic,linear or branched hydrocarbons, such as cyclohexane, hexane orisopentane, methycyclohexane, or mixtures of those solvents, for exampleaqueous solutions, unless otherwise indicated in the description of theprocesses. Such solvent mixtures may also be used in working up, forexample by chromatography or partitioning.

The compounds, including their salts, may also be obtained in the formof hydrates, or their crystals may, for example, include the solventused for crystallization. Different crystalline forms may be present.

The invention relates also to those forms of the process in which acompound obtainable as an intermediate at any stage of the process isused as starting material and the remaining process steps are carriedout, or in which a starting material is formed under the reactionconditions or is used in the form of a derivative, for example in aprotected form or in the form of a salt, or a compound obtainable by theprocess according to the invention is produced under the processconditions and processed further in situ.

All starting materials, building blocks, reagents, acids, bases,dehydrating agents, solvents and catalysts utilized to synthesize thecompounds of the present invention are either commercially available orcan be produced by organic synthesis methods known to one of ordinaryskill in the art (Houben-Weyl 4^(th) Ed. 1952, Methods of OrganicSynthesis, Thieme, Volume 21).

Typically, the compounds of Formula (I), (I-i), (I-ii), (I-iii), (I-iv),(IA), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh) and (IIi), can beprepared according to the Schemes provided infra.

Method of Preparation

The invention provides, in another aspect, a process for preparing acompound of Formula (I). The schemes, outlined below, show generalroutes for synthesizing compounds of Formula (I). In the reactionsdescribed in the schemes herein below, any reactive group present, suchas hydroxyl, amino, carbonyl or imino groups may be protected during thereaction by conventional protecting groups such as trimethylsilyl,tert-butyldimethylsilyl, benzyl, acetal, ketal etc., which are cleavedagain after the reaction.

Compounds of formula (II), wherein Lg is a leaving group such as halogenand all other symbols are defined herein above, may be reacted withalkyl lithium or Mg to provide compounds of formula (III) wherein M isselected from Li or Mg-Halogen, and all other symbols are defined hereinabove. Compounds of formula (III) may be reacted with compounds offormula (IV) wherein all symbols are defined herein above. The resultingintermediate may be dehydroxylated/dealkoxylated using reagent such astriethylsilane BF₃-etherate to provide compounds of Formula (I) whereinall symbols are defined herein above.

Compounds of formula (III), wherein M is selected from Li or Mg-Halogenand all other symbols are defined herein above, may be reacted withcompounds of formula (V) wherein Lg is a leaving group such as halogen,mesylate, tosylate or trifluoromethanesulfonyl and all other symbols aredefined herein above, to provide compounds of Formula (I) wherein allsymbols are defined herein above.

Compounds of formula (VI), wherein Lg is a leaving group such as halogenand all other symbols are defined herein above, may be reacted withalkyl lithium or Mg to provide compounds of formula (VII) wherein M isselected from Li or Mg-Halide and all other symbols are defined hereinabove. Compounds of formula (VII) may be reacted with compounds offormula (VIII) wherein all symbols are defined herein above. Theresulting intermediate may be dehydroxylated using reagent such astriethylsilane BF₃-etherate or Pd—C in presence of hydrogen atmosphereto provide compounds of Formula (I) wherein all symbols are definedherein above.

Compounds of formula (IX) wherein all symbols are defined herein abovemay be reacted with acid of formula (X) or its corresponding acidchloride wherein all symbols are defined herein above. The reaction maybe carried out in the presence of a Lewis acid followed by treating theintermediate ketone with triethylsilane BF₃-etherate to providecompounds of Formula (I) wherein all symbols are defined herein above.

Compounds of formula (XI) wherein R¹¹ is selected from hydrogen, alkyl,acyl, trifluoromethanesulfonyl and all symbols are defined herein abovemay be cyclised using OR¹¹ to obtain compounds of Formula (I) whereinring A′ has at least one ‘O’ atom and all other symbols are definedherein above.

Compounds of Formula (I) may be prepared from other compounds of Formula(I) by methods well known to one skilled in the art.

Compounds of formula (XII) wherein Lg is a leaving group such as halogenor triflate and all other symbols are defined herein above may beconverted under Suzuki coupling conditions or Buchwald couplingconditions, to obtain compounds of Formula (I) wherein ring A has atleast one substituent and all other symbols are defined herein above.Ring A′ may be formed either before or after the Suzuki couplingreaction from OR¹¹ as shown in Scheme 5.

Intermediate (II):

Compounds of formula (IIa), wherein Lg is a leaving group such ashalogen and the remaining variables are as defined herein above, may bereacted with compounds of formula (IIb) wherein M is selected fromlithium or magnesium halide and all other symbols are defined hereinabove. The resulting intermediate may be dehyroxylated/dealkoxylatedusing reagents such as triethylsilane BF₃-etherate or underhydrogenation conditions to provide compounds of formula (II) whereinall symbols are defined herein above.

Compounds of formula (IIc), wherein Lg is a leaving group such ashalogen, Z is selected from OH, NH₂ or SH, and the remaining variablesare as defined herein above, may be reacted with compounds of formula(IId) wherein all symbols are defined herein above to provideintermediate (II) wherein all symbols are defined herein above. Thereaction may be carried out in the presence of a base.

Compounds of formula (IIe) wherein Lg is a leaving group such ashalogen, and the remaining symbols are as defined herein above, may bereacted with compounds of formula (IIf), wherein Z is selected from OH,NH₂ or SH and all other symbols are defined herein above to provideintermediate (II) wherein the symbols are defined herein above. Thereaction may be carried out in the presence of a base.

Carboxylic acid of formula (IIg) or corresponding acid halide, whereinLg is a leaving group such as halogen and ring A is as defined hereinabove, may be reacted with compounds of formula (IIh), wherein allsymbols are defined herein above, to provide intermediate (II) whereinthe symbols are defined herein above. The reaction may be carried out inthe presence of a Lewis acid followed by reducing the intermediateketone using reagent such as triethylsilane BF₃-etherate or underhydrogenation conditions.

Intermediate (VIII) and (X)

Compounds of formula (VIIIa) wherein the symbols are defined hereinabove may be reacted with compounds of formula (VIIIb) wherein M isselected from lithium or magnesium halide, to provide intermediate offormula (VIIIc) which may be dehydroxylated/dealkoxylated using reagentsuch as triethylsilane BF₃-etherate or Pd—C in presence of hydrogenatmosphere to provide compounds of formula (VIIId). Compounds of formula(VIIId) may be oxidized to provide aldehyde of formula (VIII) which maybe further oxidized to provide acid of formula (X). The oxidations maybe carried out with processes known in the literature.

Compounds of formula (VIIIa), wherein all symbols are defined hereinabove, may be reacted with ketal of formula (VIIIe) wherein M isselected from lithium or magnesium halide, to provide compound offormula (VIIIf) which may be dehydroxylated/dealkoxylated using reagentsuch as triethylsilane BF₃-etherate or Pd—C in presence of hydrogenatmosphere to provide compounds of formula (VIIIg). Compounds of formula(VIIIg) may be deprotected to provide aldehyde of formula (VIII) whichmay be oxidized to provide acid of formula (X). The oxidation may becarried out with processes known in the literature.

It will be understood that the processes detailed above and elsewhereherein are solely for the purpose of illustrating the invention andshould not be construed as limiting. A process utilizing similar oranalogous reagents and/or conditions known to one skilled in the art mayalso be used to obtain a compound of the invention.

Any mixtures of final products or intermediates obtained can beseparated on the basis of the physico-chemical differences of theconstituents, in a known manner, into the pure final products orintermediates, for example by chromatography, distillation, fractionalcrystallisation, or by the formation of a salt if appropriate orpossible under the circumstances.

The following Examples are intended to illustrate the invention and arenot to be construed as being limitations thereon. If not mentionedotherwise, all evaporations are performed under reduced pressure. Thestructure of final products, intermediates and starting materials havebeen confirmed by standard analytical methods, e.g., microanalysis,melting point (m.p.) and spectroscopic characteristics, e.g. MS and NMR.Abbreviations used are those conventional in the art.

Intermediates Intermediate 1

Step I. To a stirred solution of 4H-Benzo[1,4]oxazin-3-one (2.5 g, 16.77mmol) in DMF (10 mL) was added potassium tert-butoxide (2.81 g, 25.16mmol) at 0° C. After stirring for 5 min, methyl iodide (3.54 g, 25.16mmol) was added and the reaction mixture was stirred for another 3 h.The reaction was quenched by addition of water and extracted with ethylacetate (30×2 mL). The organic layer was washed with water (20 mL), andevaporated to get a crude product 2.2 g.

Step II. To a stirred solution of 4-methyl-4H-benzo[1,4]oxazin-3-one(2.18 g, 13.37 mmol) in THF (5 mL) was added borane-tetrahydrofurancomplex (4.02 g, 46.8 mmol) at room temperature. After stirring thesolution for 2 h, the reaction mixture was refluxed for 4 h. Aftercomplete conversion, reaction mixture was quenched by adding MeOH (10mL) and evaporated the solvents. The residue obtained was extracted withethyl acetate (30×2 mL) and the organic layer was washed with water (20mL), brine (20 mL) and evaporation of solvent gave4-methyl-3,4-dihydro-2H-benzo[1,4]oxazine 2.0 g.

MS (ES) m/z 150.2 (M+1).

Intermediate 2

Step I. To a stirred suspension LiAlH₄ (7.6 g, 201 mmol) in THF at 0° C.was added 4H-benzo[1,4]oxazin-3-one (15 g, 100 mmol) in 30 mL of THF andstirred for 4 h at room temperature. After cooling, excess of LiAlH₄ wasquenched by the addition of EtOAc followed by aq. NH₄Cl solution. Theresidue was filtered through a celite bed and filtrate was concentrated.The residue was diluted with water and extracted with ethylacetate (200mL×2), combined organic layer was washed with water (100 mL) and brine(100 mL). Evaporation of the solvent resulted in3,4-dihydro-2H-benzo[1,4]oxazine (12 g) which was used as such for thenext step.

MS (ES) m/z 136 (M+1)

Step II: To a stirred solution of 3,4-dihydro-2H-benzo[1,4]oxazine (4.0g, 29.6 mmol) in DMF (20 mL) was added potassium carbonate (10.22 g,74.0 mmol). After stirring for five min. Iodo-ethane (3.5 mL, 44.4 mmol)was added and heated to 60° C. for overnight. Reaction mixture wascooled to room temperature, quenched by the addition of water (20 mL),extracted with ethyl acetate (3×25 mL). The organic layer was washedwith water (30 mL), brine (30 mL), dried over sodium sulfate,concentrated and purified by silica gel column chromatography to furnish4-ethyl-3,4-dihydro-2H-benzo[1,4]oxazine (2.7 g).

¹H NMR (400 MHz, CD₃OD): δ 1.10 (t, J=6.8 Hz, 3H), 3.26-3.33 (m, 4H),4.16 (t, J=4.4 Hz, 2H), 4.40 (s, 2H), 6.52-6.58 (m, 1H), 6.60-6.80 (m,3H).

MS (ES) m/z 163.2 (M+1)

Intermediate 3

Step I. To a stirred solution of 3,4-dihydro-2H-benzo[1,4]oxazine (5 g,37.0 mmol) in DMF (20 mL) was added potassium tert-butoxide (6.22 g,55.55 mmol) at 0° C. After stirring for 5 min, bromo-cyclopropane (4.44mL, 55.55 mmol) was added and the reaction mixture was stirred foranother 4 h at room temperature. The reaction was quenched by additionof water and extracted with ethyl acetate (50×2 mL). The organic layerwas washed with water (20 mL), concentrated and purified by silica gelcolumn chromatography to furnish4-Cyclopropyl-3,4-dihydro-2H-benzo[1,4]oxazine (4.42 g).

MS (ES) m/z 176 (M+1).

Intermediate 4

Step I. To a stirred solution of 2-aminophenol (10 g, 9.2 mmol) in DCM(92 mL) at 0° C. was added 2-bromoisobutyryl bromide (11.4 mL, 9.17mmol) followed by triethyl amine (12.7 mL, 9.2 mmol) and stirred thereaction mixture at 0° C. for 4 h. Reaction mixture was diluted with DCM100 mL and then washed with water 100 mL dried over sodium sulfate,concentrated on rotavap to give2-Bromo-N-(2-hydroxy-phenyl)-2-methyl-propionamide (21.8 g) brown solidwhich was used for next reaction without purification

Step II. To a stirred solution of2-Bromo-N-(2-hydroxy-phenyl)-2-methyl-propionamide (21.8 g, 84.4 mmol)in DMF (85 mL) at 25° C. was added potassium carbonate (23.32 g, 168.99mmol) and stirred the reaction mixture at 80° C. for 4 h. After TLCreaction mixture was filtered through celite and diluted with ethylacetate 500 mL and then washed with water (100 mL×3), brine (100 mL),dried over anhydrous sodium sulfate, concentrated to give2,2-dimethyl-4H-benzo[1,4]oxazin-3-one (12.64 g) as brown solid whichwas purified by column chromatography to furnish 8.5 g pure compound.

MS (EI) m/z 178.2 (M+1)

Step III. To a stirred solution of LAH (3.01 g, 79.10 mmol) in THF (80mL) at 0° C. was added 2,2-dimethyl-4H-benzo[1,4]oxazin-3-one (7.00 g,39.5 mmol) in portions and stirred the reaction mixture at 25° C. for 1h and then 50° C. for 3 h. Reaction mixture was quenched by the additioncold saturated sodium sulfate solution and it was filtered throughcelite and extracted with DCM (100 mL×2), washed with brine (50 mL),dried over sodium sulfate, concentrated to give2,2-dimethyl-3,4-dihydro-2H-benzo[1,4]oxazine (6.09 g), which was usedas such for the next reaction without purification

MS (EI) m/z 164.2 (M+1)

Step IV. To a stirred solution of2,2-dimethyl-3,4-dihydro-2H-benzo[1,4]oxazine (6 g, 36.8 mmol) in DCM(75 mL) at 0° C. was added trifluoroacetic anhydride (6.2 mL, 44.2 mmol)followed by triethyl amine (6.2 mL, 44.2 mmol) and stirred the reactionmixture at 0° C. for 2 h. Reaction mixture was diluted with DCM (100 mL)and then washed with water (100 mL×2), brine (100 mL), dried overanhydrous sodium sulfate, concentrated on to give1-(2,2-dimethyl-2,3-dihydro-benzo[1,4]oxazin-4-yl)-2,2,2-trifluoro-ethanone(9.46 g) as brown solid which was purified by column chromatography tofurnish 8.7 g pure product.

MS (EI) m/z 260.2 (M+1)

¹H NMR (400 MHz, CDCl₃): δ 1.38 (s, 6H), 3.65 (s, 2H), 6.86-6.96 (m,2H), 7.12-7.16 (m, 1H), 7.97 (d, 1H).

Intermediate 5

To a stirred solution of 6-bromo-1,2,3,4-tetrahydro-quinoline (3.00 g,12.1 mmol) in dimethylformamide (25 mL) was added potassium carbonate(3.3 g, 24.1 mmol), sodium iodide (0.905 g, 6.0 mmol) and4-methoxybenzyl chloride (2.5 mL, 18.1 mmol) and heated at 50° C. After18 h, reaction mixture was cooled to room temperature and quenched bythe addition of water and extracted with ethyl acetate (2×20 mL). Theorganic layer was washed with water (2×20 mL), brine (20 mL), dried oversodium sulfate, concentrated and purified by the silica gel columnchromatography to furnish6-bromo-1-(4-methoxy-benzyl)-1,2,3,4-tetrahydro-quinoline (2.5 g).

¹H NMR (400 MHz, CDCl₃): δ 1.96-2.02 (m, 2H), 2.78 (t, J=6.0 Hz, 2H),3.46 (t, J=5.2 Hz, 2H), 3.80 (s, 3H), 4.40 (s, 2H), 6.38 (d, J=8.4 Hz,1H), 6.86 (d, J=8.4 Hz, 2H), 7.04 (d, J=8.8 Hz, 1H), 7.07 (s, 1H), 7.15(d, J=8.4 Hz, 2H).

MS (ES) m/z 332.1, 334.1 (M+1)

EXAMPLES Example 1(2S,3R,4R,5S,6R)-2-[4-Chloro-3-(4-methyl-3,4-dihydro-2Hbenzo[1,4]oxazin-7-ylmethyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol

Step I. To a stirred solution of4-methyl-3,4-dihydro-2H-benzo[1,4]oxazine (2.00 g, 13.4 mmol) indichloromethane (30 mL) was added 5-bromo-2-chlorobenzoyl chloride (4.07g, 16.1 mmol) in dichloromethane (20 mL) at 0° C. followed by additionof AlCl₃ (2.14 g, 16.1 mmol). After 2 h, the reaction mixture wasbrought to room temperature and stirred overnight. The reaction wasquenched by pouring over crushed ice and extracted with dichloromethane(30×2 mL). The organic layer was washed with aq. NaHCO₃ (20 mL), H₂O (20mL) and to obtain a crude product 3.0 g.

Step II. To the crude product (0.9 g, 2.45 mmol) in 1:2 mixture of1,2-dichloroethane/MeCN (12 mL) was added Et₃SiH (0.83 mL, 5.16 mmol)and BF3.OEt2 (0.37 mL, 3.19 mmol) simultaneously at 20° C. Afterstirring overnight, the reaction mixture was heated at 50° C. for 2 h.The reaction was quenched by the addition of aq. NaHCO₃ (5 mL). Thevolatiles were evaporated under reduced pressure; the resulting mixturewas extracted with dichloromethane (2×20 mL), washed with brine (5 mL),dried over sodium sulfate, concentrated and purified by silica gelcolumn chromatography to furnish7-(5-bromo-2-chloro-benzyl)-4-methyl-3,4-dihydro-2H-benzo[1,4]oxazine(0.375 g).

¹H NMR (400 MHz, CDCl₃): δ 2.89 (s, 3H), 3.27 (s, 2H), 3.93 (s, 2H),4.32 (t, J=3.6 Hz, 2H), 6.61 (s, 1H), 6.64-6.74 (m, 2H) 7.19-7.32 (m,3H).

MS (ES) m/z 351.8 (M+1)

Step III: To a stirred solution of7-(5-bromo-2-chloro-benzyl)-4-methyl-3,4-dihydro-2H-benzo[1,4]oxazine(0.37 g, 1.06 mmol) in THF toluene (5 mL of 1:2 mixture) was added 1.6 Msolution of n BuLi in hexanes (0.68 mL, 1.06 mmol) at 78° C. Thereaction mixture was stirred for 1 h and then transferred to a stirredsolution of 2,3,4,6-tetrakis-O-(trimethylsilyl)-D-glucopyranone (0.49 g,1.06 mmol) in toluene (5 mL) at −78° C. After stirring for 4 h, 0.6 Nmethanesulfonic acid in methanol (5 mL) was added and stirred thereaction mixture for 12 h at room temperature. Reaction was quenched bythe addition of aq. NaHCO₃ solution (5 mL) and extracted withdichloromethane (3×10 mL), dried over sodium sulfate, concentrated andpurified by silica gel column chromatography to furnish(2S,3R,4S,5S,6R)-2-[4-chloro-3-(4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-7-ylmethyl)-phenyl]-6-hydroxymethyl-2-methoxy-tetrahydro-pyran-3,4,5-triol(0.178 g).

¹H NMR (400 MHz, CD₃OD): δ 2.82 (s, 3H), 3.08 (s, 3H), 3.10 (d, J=10.0Hz, 1H), 3.18 (t, J=4.0 Hz, 2H), 3.42 (t, J=9.6 Hz, 1H), 3.55-3.62 (m,1H), 3.75 (t, J=9.2 Hz, 1H), 3.82 (dd, J=12.0, 5.6 Hz, 1H), 3.90 (d,J=14.8 Hz, 1H), 3.94 (d, J=10.4 Hz, 1H), 4.02 (d, J=15.2 Hz, 1H), 4.23(t, J=4.4 Hz, 2H), 6.51 (s, 1H), 6.60-6.68 (m, 2H), 7.35 (d, J=8.4 Hz,1H), 7.45 (d, J=8.4 Hz, 1H), 7.53 (s, 1H).

MS (ES) m/z 466.3 (M+1).

Step IV: To a stirred solution of(2S,3R,4S,5S,6R)-2-[4-chloro-3-(4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-7-ylmethyl)-phenyl]-6-hydroxymethyl-2-methoxy-tetrahydro-pyran-3,4,5-triol(0.17 g, 0.37 mmol) in acetonitrile-dichloromethane mixture (1:1mixture, 6 mL) was added boron trifluoride diethyletharate complex (0.09mL, 0.75 mmol), and triethylsilane (0.24 mL, 1.50 mmol) at 10° C. Afterstirring for 4 h at the same temperature, the reaction was quenched withaq. NaHCO₃ (4 mL). The volatiles were evaporated under reduced pressure;the resulting mixture was extracted with dichloromethane (2×20 mL),washed with brine (3 mL), dried over sodium sulfate, concentrated andpurified by preparative HPLC to furnish(2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-methyl-3,4-dihydro-Hbenzo[1,4]oxazin-7-ylmethyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol(40 mg).

¹H NMR (400 MHz, CD₃OD): δ 2.80 (s, 3H), 3.15 (t, J=4.4 Hz, 2H),3.25-3.34 (m, 1H), 3.35-3.48 (m, 3H), 3.68 (dd, J=12.0, 5.6 Hz, 1H),3.86 (d, J=8.4 Hz, 1H), 3.92 (Abq, J=15.2 Hz, 2H), 4.07 (d, J=9.6 Hz,1H), 4.21 (t, J=4.4 Hz, 2H), 6.50 (d, J=0.8 Hz, 1H), 6.66 (d, J=8.4 Hz,1H), 6.64 (dd, J=8.4, 1.2 Hz, 1H), 7.24 (dd, J=8.0, 1.6 Hz, 1H), 7.29(s, 1H), 7.33 (d, J=8.0, 1H).

MS (ES) m/z 436.0 (M+1).

Following examples were prepared by using the procedures described forexample 1.

Example No. Structure/IUPAC name Spectral data 2

¹H NMR (400 MHz, CD₃OD): δ 1.08 (t, J = 6.8 Hz, 3H), 3.15-3.48 (m, 8H),3.66 (d, J = 11.2 Hz, 1H), 3.85 (d, J = 12.0 Hz, 1H), 3.90 (Abq, 15.2Hz, 2H), 4.06 (d, J = 9.2 Hz, 1H), 4.14 (s, 2H), 6.49 (s, 1H), 6.60 (s,2H), 7.23 (d, J = 8.0 Hz, 1H), 7.28 (s, 1H), 7.31 (d, J = 8.0 Hz, 1H),.MS (ES) m/z 450.3 (M + 1). 3

¹H NMR (400 MHz, CD₃OD): δ 0.54 (s, 2H), 0.75 (d, J = 2.0 Hz, 2H), 2.12(m, 1H), 3.15-3.50 (m, 6H), 3.66 (dd, J = 11.6, 4.0 Hz, 1H), 3.85 (d, J= 10.8 Hz, 1H), 3.91 (Abq, 15.2 Hz, 2H), 4.05 (d, J = 9.2 Hz, 1H), 4.15(s, 2H), 6.48 (s, 1H), 6.61 (d, J = 8.0 Hz, 1H), 7.05 (d, J = 8.0 Hz,1H), 7.23 (d, J = 8.0 Hz, 1H), 7.23 (s, 1H), 7.31 (d, J = 8.4 Hz, 1H),.MS (ES) m/z 462.3 (M + 1).

Example 4(2S,3R,4R,5S,6R)-2-[3-(4-Benzyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-4-chloro-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol

Step I. To a stirred solution of1-(2,3-dihydro-benzo[1,4]oxazin-4-yl)-2,2,2-trifluoro-ethanone (6.5 g,28.1 mmol) in dichloromethane (45 mL) was added 5-bromo-2-chlorobenzoylchloride (8.54 g, 33.7 mmol) in dichloromethane (35 mL) and AlCl₃ (5.61g, 42.2 mmol) at 0° C. After 2 h, the reaction mixture was brought toroom temperature and stirred overnight. The reaction was quenched bypouring over crushed ice and extracted with dichloromethane (2×50 mL).The organic layer was washed with aq. NaHCO₃ (30 mL), H₂O (20 mL), andthe solvent evaporated to get the crude product which was purified bysilica gel column chromatography to give1-[6-(5-bromo-2-chloro-benzoyl)-2,3-dihydro-benzo[1,4]oxazin-4-yl]-2,2,2-trifluoro-ethanone(10.0 g).

¹H NMR (400 MHz, CDCl₃): 4.03 (t, J=4.0 Hz, 2H), 4.48 (t, J=4.2 Hz, 2H),7.04 (d, J=8.4 Hz, 1H), 7.34 (d, J=8.4 Hz, 1H), 7.50 (d, J=2.0 Hz, 1H),7.55 (dd, J=8.4, 2.0 Hz, 1H), 7.68 (d, J=8.4 Hz, 1H) 8.42 (broad s, 1H).

MS (ES) m/z 450 (M+2)

Step II. To a stirred solution of1-[6-(5-bromo-2-chloro-benzoyl)-2,3-dihydro-benzo[1,4]oxazin-4-yl]-2,2,2-trifluoro-ethanone(1.0 g, 2.23 mmol) in 1:2 of 1,2-dichloroethane/MeCN (12 mL) was addedEt₃SiH (0.755 mL, 4.68 mmol) and BF₃.OEt₂ (0.34 mL, 2.90 mmol)simultaneously at 20° C. The reaction mixture was heated at 50° C. for 4h and quenched by the addition of aq. NaHCO₃ (10 mL). The volatiles wereevaporated under reduced pressure; the resulting mixture was extractedwith dichloromethane (2×20 mL), washed with brine (5 mL), dried oversodium sulfate, concentrated and was purified by silica gel columnchromatography to furnish1-[6-(5-bromo-2-chloro-benzyl)-2,3-dihydro-benzo[1,4]oxazin-4-yl]-2,2,2-trifluoro-ethanone(0.60 g).

¹H NMR (400 MHz, DMSO): δ 3.96 (t, J=4.0 Hz, 2H), 3.99 (s, 2H), 4.37 (t,J=4.4 Hz, 2H), 6.69 (d, J=8.4 Hz, 1H), 7.03 (d, J=7.6 Hz, 1H), 7.40 (d,J=8.4 Hz, 1H), 7.46 (dd, J=8.4, 2.0 Hz, 1H), 7.53 (d, J=2.4 Hz, 1H),7.82 (broad s, 1H).

Step III: To a stirred solution of1-[6-(5-bromo-2-chloro-benzyl)-2,3-dihydro-benzo[1,4]oxazin-4-yl]-2,2,2-trifluoro-ethanone(8.6 g, 19.8 mmol) in ethanol (40 mL) was added NaBH₄ portion wise andthe reaction mixture was stirred overnight. The excess of NaBH₄ wasquenched by adding aq. HCl. Ethanol was evaporated and the residue waspartitioned between dichloromethane and water. Organic layer was washedwith brine, water, dried over sodium sulfate followed by evaporation ofsolvent furnished6-(5-bromo-2-chloro-benzyl)-3,4-dihydro-2H-benzo[1,4]oxazine (6.1 g).

Step IV: To a stirred solution of6-(5-bromo-2-chloro-benzyl)-3,4-dihydro-2H-benzo[1,4]oxazine (8.0 g,23.66 mmol) in DMF (35 mL) was added potassium carbonate (6.53 g, 36.0mmol), benzyl bromide (4.33 mL, 35.50 mmol) and heated to 50° C. for 8h. Reaction mixture was cooled to room temperature, quenched by theaddition of water (50 mL), extracted with ethyl acetate (3×20 mL). Theorganic layer was washed with water (50 mL), brine (50 mL), dried oversodium sulfate, concentrated and purified by silica gel columnchromatography to furnish4-benzyl-6-(5-bromo-2-chloro-benzyl)-3,4-dihydro-2H-benzo[1,4]oxazine(7.0 g).

¹H NMR (400 MHz, CD₃OD): δ 3.40 (t, J=4.4 Hz, 2H), 3.85 (s, 2H), 4.24(t, J=4.4 Hz, 2H), 4.40 (s, 2H), 6.40 (dd, J=8.0, 2.0 Hz, 1H), 6.45 (d,J=2.0 Hz, 1H), 6.66 (d, J=8.0, Hz, 1H), 7.20-7.36 (m, 8H).

MS (ES) m/z 429.9 (M+2).

Step V: To a stirred solution of4-benzyl-6-(5-bromo-2-chloro-benzyl)-3,4-dihydro-2H-benzo[1,4]oxazine(7.0 g, 16.3 mmol) in THF-toluene (40 mL of 1:2 mixture) was added 1.6 Msolution of n-BuLi in hexanes (10.46 mL, 16.35 mmol) at −78° C. Thereaction mixture was stirred for 1 h and then transferred to a stirredsolution of 2,3,4,6-tetrakis-O-(trimethylsilyl)-D-glucopyranone (7.62 g,16.35 mmol) in toluene (25 mL) at −78° C. After stirring for 4 h., 0.6 Nmethanesulfonic acid in methanol (50 mL) was added and stirred for 12 hat room temperature. Reaction was quenched by the addition of aq.saturated sodium bicarbonate solution (25 mL) and extracted withdichloromethane (3×25 mL), dried over sodium sulfate, concentrated andpurified by silica gel column chromatography to furnish(2S,3R,4S,5S,6R)-2-[3-(4-benzyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-4-chloro-phenyl]-6-hydroxymethyl-2-methoxy-tetrahydro-pyran-3,4,5-triol(5.0 g).

Step VI: To a stirred solution of(2S,3R,4S,5S,6R)-2-[3-(4-benzyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-4-chloro-phenyl]-6-hydroxymethyl-2-methoxy-tetrahydro-pyran-3,4,5-triol(5.0 g, 9.24 mmol) in acetonitrile-dichloromethane mixture (1:1 mixture,40 mL) was added boron trifluoride diethyletharate complex (2.34 mL,18.48 mmol), and triethylsilane (5.95 mL, 36.9 mmol) at −10° C. Afterstirring for 4 h at the same temperature, the reaction was quenched withaq. saturated sodium bicarbonate solution (15 mL). The volatiles wereevaporated under reduced pressure; the resulting mixture was extractedwith dichloromethane (2×30 mL). The organic layer was washed with brine(10 mL), dried over sodium sulfate, concentrated and purified bypreparative HPLC to furnish(2S,3R,4R,5S,6R)-2-[3-(4-benzyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-4-chloro-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol(3.5 g).

¹H NMR (400 MHz, CD₃OD): δ 3.20-3.50 (m, 6H), 3.68 (dd, J=12.0, 4.4 Hz,1H), 3.75-3.95 (m, 3H), 4.03 (d, J=9.2 Hz, 1H), 4.16 (t, J=3.6 Hz, 2H),4.35 (s, 2H), 6.37 (d, J=8.0 Hz, 1H), 6.54 (s, 1H), 6.57 (d, J=0.8 Hz,1H), 7.15-7.62 (m, 8H).

MS (ES) m/z 511.8 (M+1).

Following examples were prepared by using the procedures described forexample 4.

Example No. Structure/IUPAC name Spectral data 5

¹H NMR (400 MHz, CD₃OD): δ 3.31 (s, 3H), 3.38-3.52 (m, 3H), 3.70 (dd, J= 11.2, 4.0 Hz, 1H), 3.78 (s, 3H), 3.88 (d, 11.6 Hz, 1H), 3.91 (Abq,14.8 Hz, 2H), 4.08 (d, J = 9.2 Hz, 1H), 4.17 (s, 2H), 4.31 (s, 2H), 6.41(d, J = 7.6 Hz, 1H), 6.59 (d, J = 7.6 Hz, 2H), 6.86 (d, J = 8.0 Hz, 2H),7.17 (d, J = 8.0 Hz, 2H), 7.22-7.38 (m, 3H). MS (ES) m/z 541.8 (M + 1).6

¹H NMR (400 MHz, CD₃OD): δ 1.26 (s, 6H), 3.35-3.46 (m, 2H), 3.64- 3.70(m, 1H), 3.80-3.91 (m, 3H), 4.05 (d, 1H), 4.38 (s, 2H), 4.56 (s, 4H),6.46-6.52 (m, 1H), 6.54-6.57 (m, 2H), 7.19-7.28 (m, 8H). MS (ES) m/z540.2 (M + 1)

Examples 7-8

Step I. To a stirred suspension LiAlH₄ (7.6 g, 201 mmol) in THF (70 mL)at 0° C. was added 4H-benzo[1,4]oxazin-3-one (15 g, 100 mmol) in 30 mLof THF and the mixture was stirred for 4 h at room temperature. Aftercooling, excess of LiAlH₄ was quenched by the addition of ethyl acetate(30 mL) followed by aq. NH₄Cl solution. The mixture was filtered througha celite bed and the filtrate was concentrated under reduced pressureand extracted with ethyl acetate (3×30 mL). The combined organic layerswere washed with brine (30 mL) and dried over Na₂SO₄. Evaporation of thesolvent resulted in benzoxazine (12 g) which was used as such for thenext step.

MS (ES) m/z 136 (M+1)

Step II. To an ice-cold solution of benzoxazine (4.5 g, 33.3 mmol) indichloromethane (25 mL) was added trifluoroacetic anhydride (6.95 mL,49.9 mmol) and the reaction mixture was stirred for 2 h then quenched bythe addition of aq. NaHCO₃ solution. The mixture was partitioned betweendichloromethane and water. The organic layer was separated, and theaqueous layer was extracted with dichloromethane. The combined organiclayers were washed with brine, dried over Na₂SO₄, and concentrated toyield 1-(2,3-dihydro-benzo[1,4]oxazin-4-yl)-2,2,2-trifluoro-ethanone(6.5 g).

MS (ES) m/z 232 (M+1)

Step III: To a stirred solution of 2-bromo-5-chlorobenzoic acid (8 g,34.0 mmole) in dichloromethane (35 mL) was added DMF (1 mL) and oxalylchloride (3.54 mL, 37.4 mmol) drop wise at 0° C. After completeaddition, the reaction mixture was stirred at room temperature for 3 h.The volatiles were evaporated under reduced pressure to furnish2-bromo-5-chloro-benzoyl chloride (8.5 g). The crude product was usedwithout further purification.

To an ice cooled solution of 5-bromo-2-chlorobenzoyl chloride indichloromethane (35 mL) was added1-(2,3-dihydro-benzo[1,4]oxazin-4-yl)-2,2,2-trifluoro-ethanone (6.5 g,28.1 mmol) in dichloromethane (45 mL) followed by AlCl₃ (5.61 g, 42.2mmol) portion wise. After 2 h, the reaction mixture was brought to roomtemperature and stirred overnight. The reaction was quenched by pouringit over crushed ice. The resulting mixture was extracted withdichloromethane. The organic layer was washed with aq. NaHCO₃ (100 mL)and water (100 mL), and the solvent was evaporated to yield the crudeproduct which was recrystallized from hot ethylacetate to furnish1-[6-(5-bromo-2-chloro-benzoyl)-2,3-dihydro-benzo[1,4]oxazin-4-yl]-2,2,2-trifluoro-ethanone(10.0 g).

¹H NMR (400 MHz, CDCl₃): 4.03 (t, J=4.0 Hz, 2H), 4.48 (t, J=4.2 Hz, 2H),7.04 (d, J=8.4 Hz, 1H), 7.34 (d, J=8.4 Hz, 1H), 7.50 (d, J=2.0 Hz, 1H),7.55 (dd, J=8.4, 2.0 Hz, 1H), 7.68 (d, J=8.4 Hz, 1H) 8.42 (broad s, 1H).

MS (ES) m/z 450 (M+2)

Step IV. To a stirred solution of1-[6-(5-bromo-2-chloro-benzoyl)-2,3-dihydro-benzo[1,4]oxazin-4-yl]-2,2,2-trifluoro-ethanone(36 g, 80.35 mmol) in 1,2-dichloroethane:MeCN 1:2 (180 mL) was addedBF₃.OEt₂ (13.2 mL, 104 mmol) and Et₃SiH (26.9 mL, 168.7 mmol) at 0° C.The reaction mixture was stirred overnight at room temperature thenquenched by the addition of aq. NaHCO₃ (˜200 mL). The resulting mixturewas extracted with ethyl acetate (3×200 mL), and the combined organiclayers were washed with brine (200 mL) and dried over sodium sulfate.Crude product obtained after evaporation of solvent was purified bysilica gel column chromatography to furnish1-[6-(5-bromo-2-chloro-benzyl)-2,3-dihydro-benzo[1,4]oxazin-4-yl]-2,2,2-trifluoro-ethanone(30 g).

¹H NMR (400 MHz, DMSO): δ 3.96 (t, J=4.0 Hz, 2H), 3.99 (s, 2H), 4.37 (t,J=4.4 Hz, 2H), 6.69 (d, J=8.4 Hz, 1H), 7.03 (d, J=7.6 Hz, 1H), 7.40 (d,J=8.4 Hz, 1H), 7.46 (dd, J=8.4, 2.0 Hz, 1H), 7.53 (d, J=2.4 Hz, 1H),7.82 (br s, 1H).

Step V: To a stirred solution of1-[6-(5-bromo-2-chloro-benzyl)-2,3-dihydro-benzo[1,4]oxazin-4-yl]-2,2,2-trifluoro-ethanone(8.6 g, 19.8 mmol) in ethanol (40 mL) was added NaBH₄ (1.5 g, 39.0 mmol)portion wise and the reaction mixture was stirred overnight. Excess ofNaBH₄ was quenched by adding aq. NH₄CI, and ethanol was evaporated. Theresidue was partitioned between ethyl acetate and water, and the organiclayer was separated, washed with brine (40 mL) and dried over sodiumsulphate. Crude product obtained after evaporation of solvent waspurified by silica gel column chromatography to furnish6-(5-bromo-2-chloro-benzyl)-3,4-dihydro-2H-benzo[1,4]oxazine (6.1 g).

MS (ES) m/z 340 (M+2).

Step VI: To a stirred solution of6-(5-bromo-2-chloro-benzyl)-3,4-dihydro-2H-benzo[1,4]oxazine (8.0 g,23.66 mmol) in DMF (35 mL) was added potassium carbonate (6.53 g, 47.3mmol), and benzyl bromide (4.33 mL, 35.50 mmol). The reaction mixturewas heated to 60° C. for 8 h, then cooled to room temperature andquenched by the addition of ice-cold water (50 mL). The resultingmixture was extracted with ethyl acetate (3×30 mL), and the combinedorganic layers were washed with water (50 mL) and brine (50 mL), thendried over sodium sulfate. The sodium sulfate was filtered off and thefiltrate was concentrated to crude product which was purified by silicagel column chromatography to furnish4-benzyl-6-(5-bromo-2-chloro-benzyl)-3,4-dihydro-2H-benzo[1,4]oxazine(7.0 g).

¹H NMR (400 MHz, CD₃OD): δ 3.40 (t, J=4.4 Hz, 2H), 3.85 (s, 2H), 4.24(t, J=4.4 Hz, 2H), 4.40 (s, 2H), 6.40 (dd, J=8.0, 2.0 Hz, 1H), 6.45 (d,J=2.0 Hz, 1H), 6.66 (d, J=8.0, Hz, 1H), 7.20-7.36 (m, 8H).

MS (ES) m/z 430 (M+2).

Step VII: To a stirred solution of4-benzyl-6-(5-bromo-2-chloro-benzyl)-3,4-dihydro-2H-benzo[1,4]oxazine(7.0 g, 16.3 mmol) in THF-toluene 1:2 (40 mL) was added 1.6 M solutionof n-BuLi in hexanes (10.46 mL, 16.35 mmol) at −78° C. The reactionmixture was stirred for 1 h and then transferred to a stirred solutionof 2,3,4,6-tetrakis-O-(trimethylsilyl)-D-glucopyranone (7.62 g, 16.35mmol) in toluene (25 mL) at −78° C. After stirring for 1 h, 0.6 Nmethanesulfonic acid in methanol (70 mL) was added and the reactionmixturer was stirred for 12 h at room temperature then quenched by theaddition of aq. saturated sodium bicarbonate solution (˜25 mL). Theresulting mixture was extracted with ethyl acetate (3×100 mL) and thecombined organic layers were dried over sodium sulfate, concentrated andpurified by silica gel column chromatography to furnish(2S,3R,4S,5S,6R)-2-[3-(4-benzyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-4-chloro-phenyl]-6-hydroxymethyl-2-methoxy-tetrahydro-pyran-3,4,5-triol(5.0 g).

Example 7(2S,3R,4R,5S,6R)-2-[3-(4-benzyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-4-chloro-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol

Step VIII: To a stirred solution of(2S,3R,4S,5S,6R)-2-[3-(4-benzyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-4-chloro-phenyl]-6-hydroxymethyl-2-methoxy-tetrahydro-pyran-3,4,5-triol(5.0 g, 9.24 mmol) in acetonitrile-dichloromethane mixture 1:1 (40 mL)was added boron trifluoride diethyletharate complex (2.34 mL, 18.48mmol), and triethylsilane (5.95 mL, 36.9 mmol) at −5° C. After stirringfor 4 h at the same temperature, the reaction was quenched with aq.saturated sodium bicarbonate solution (15 mL). The volatiles wereevaporated under reduced pressure, and the resulting mixture wasextracted with dichloromethane (2×30 mL). The organic layers werecombined and washed with brine (10 mL), dried over sodium sulfate,concentrated and purified by preparative HPLC to furnish(2S,3R,4R,5S,6R)-2-[3-(4-benzyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-4-chloro-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol(3.5 g).

¹H NMR (400 MHz, CD₃OD): δ 3.20-3.50 (m, 6H), 3.68 (dd, J=12.0, 4.4 Hz,1H), 3.75-3.95 (m, 3H), 4.03 (d, J=9.2 Hz, 1H), 4.16 (t, J=3.6 Hz, 2H),4.35 (s, 2H), 6.37 (d, J=8.0 Hz, 1H), 6.54 (s, 1H), 6.57 (d, J=0.8 Hz,1H), 7.15-7.62 (m, 8H).

MS (ES) m/z 511.8 (M+1)

Example 8(2S,3R,4R,5S,6R)-2-[4-Chloro-3-(3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol

Step IX: To a solution of(2S,3R,4R,5S,6R)-2-[3-(4-benzyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-4-chloro-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol(2.4 g, 4.68 mmol) in methanol (15 mL) was added 10% palladium oncharcoal (240 mg) and 0.05 mL conc. HCl. The reaction mixture wasstirred under hydrogen atmosphere for 2 h then filtered through celitebed (which was washed with methanol). The resulting filtrate wasconcentrated to a residue which was purified by preparative HPLC tofurnish(2S,3R,4R,5S,6R)-2-[4-chloro-3-(3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol(1.6 g).

¹H NMR (400 MHz, CD₃OD): δ 3.24-3.34 (m, 2H), 3.35-3.49 (m, 4H), 3.69(dd, J=12.0, 5.6 Hz, 1H), 3.88 (dd, J=11.6, 2.0 Hz, 1H), 3.93 (ABq,J=15.2 Hz, 2H), 4.08 (d, J=9.6 Hz, 1H), 4.15 (t, J=4.4 Hz, 2H),6.42-6.50 (m, 2H), 6.58 (d, J=8.0 Hz, 1H), 7.26 (dd, J=8.0, 2.4 Hz, 1H),7.30 (d, J=2.0 Hz, 1H), 7.33 (d, J=8.0 Hz, 1H).

Example 9(2S,3R,4R,5S,6R)-2-[4-Chloro-3-(4-ethyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol

To a stirred solution of(2S,3R,4R,5S,6R)-2-[4-chloro-3-(3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol(0.1 g, 0.23 mmol) in DMF (2 mL) was added potassium carbonate (0.065 g,0.47 mmol), ethyl iodide (0.028 mL, 0.35 mmol) and stirred the solutionat 20° C. for 2 h. Reaction mixture was quenched by the addition ofwater (2 mL), extracted with dichloromethane (3×5 mL). The organic layerwas washed with water (5 mL), brine (5 mL), dried over sodium sulfate,concentrated and purified by preparative HPLC to furnish(2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol(20 mg).

¹H NMR (400 MHz, CD₃OD): δ 1.17 (t, J=6.8 Hz, 3H), 3.20-3.50 (m, 6H),3.52-3.62 (m, 2H), 3.63 (dd, J=11.2, 5.6 Hz, 1H), 3.77 (d, J=11.2 Hz,1H), 3.88 (abq, J=15.2 Hz, 2H), 4.06 (d, J=9.6 Hz, 1H), 4.15 (t, J=3.6Hz, 2H), 6.43 (d, J=8.8 Hz, 1H), 6.46 (s, 1H), 6.57 (d, J=7.6 Hz, 1H),7.23 (d, J=8.0 Hz, 1H), 7.27 (s, 1H), 7.34 (d, J=8.4 Hz, 1H). MS (ES)m/z 450 (M+1).

Following examples were prepared using the procedures described forexample 9.

Example No. Structure/IUPAC name Spectral data 10

¹H NMR (400 MHz, CD₃OD): δ 0.118 (s, 2H), 0.51 (d, J = 6.8 Hz, 2H),1.00-1.10 (m, 1H), 3.20- 3.60 (m, 8H), 3.60-3.75 (m, 1H), 3.82 (d, J =10.0 Hz, 1H) 3.94 (abq, 15.2 Hz, 2H), 4.07 (d, J = 9.6 Hz, 1H), 4.15 (t,J = 4.0, 2H), 6.43 (d, J =8.0 Hz, 1H), 6.45 (s, 1H), 6.58 (d, J = 8.0Hz, 1H), 7.24 (dd, J = 8.0, 1.2 Hz, 1H), 7.25 (s, 1H) 7.34 (d, J = 8.0Hz, 1H),. MS (ES) m/z 476.3 (M + 1). 11

¹H NMR (400 MHz, CD₃OD): δ 3.20-3.32 (m, 3H), 3.37 (s, 3H), 3.40-3.55(m, 3H), 3.61 (dd, J = 10.8, 5.2 Hz, 1H), 3.71 (d, J = 10.8 Hz, 1H),3.93 (abq, 15.2 Hz, 2H), 4.06 (d, J = 9.6 Hz, 1H), 4.15 (t, J = 4.0,2H), 6.43 (d, J = 8.8 Hz, 1H), 6.45 (s, 1H), 6.57 (d, J = 8.0 Hz, 1H),7.23 (d, J = 8.4 Hz, 1H), 7.26 (s, 1H) 7.33 (d, J = 8.4 Hz, 1H),. MS(ES) m/z 435 (M + 1). 12

¹H NMR (400 MHz, CD₃OD): δ 1.25 (t, J = 6.4 Hz, 3H), 3.30-3.50 (m, 3H),3.66 (d, J = 11.6 Hz, 1H), 3.84 (d, J = 11.2 Hz, 3H), 3.99 (Abq, J =15.2 Hz, 2H), 4.07 (d, J = 9.6 Hz, 1H), 4.12-4.26 (m, 3H), 6.58 (s, 2H),6.72 (d, J = 8.4 Hz, 1H), 6.82 (d, J = 7.6 Hz, 1H), 7.25 (d, J = 7.6 Hz,1H), 7.32 (d, J = 6.4 Hz, 2H) 7.61 (s, 1H),. MS (ES) m/z 494.3 (M + 1).13

¹H NMR (400 MHz, CD₃OD): δ 2.25 (s, 3H), 3.25-3.55 (m, 4H), 3.71 (dd, J= 11.6, 4.4 Hz, 1H), 3.88 (d, J = 13.6 Hz, 3H), 4.06 (s, 2H), 4.12 (d, J= 9.6 Hz, 1H), 4.26 (s, 2H), 6.81 (d, J = 8.0 Hz, 2H), 6.98 (br s, 1H),7.29 (d, J = 8.0 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.39 (s, 1H) MS (ES)m/z 464.2 (M + 1).

Example 14(2S,3R,4R,5S,6R)-2-{4-Chloro-3-[1-(4-methoxy-benzyl)-1,2,3,4-tetrahydro-quinolin-6-ylmethyl]-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol

Step I: To a cooled solution of6-bromo-1-(4-methoxy-benzyl)-1,2,3,4-tetrahydro-quinoline (2.5 g, 7.5mmol) in THF (30 mL) was added 1.6 M n-butyl lithium in hexanes (4.7 mL,7.5 mmol) at −78° C., stirred for 30 min. This was transferred to astirred solution of 5-bromo-2-chlorobenzaldehyde (1.73 g, 7.9 mmol) inTHF (30 mL) at −78° C. After stirring for 30 min, reaction was quenchedby the addition of saturated aqueous solution of ammonium chloride andextracted with ethyl acetate (2×50 mL). The ethyl acetate layer waswashed with water, brine, dried over sodium sulphate, and concentrated.The resulting residue was purified by silica gel column chromatographyto give(5-bromo-2-chloro-phenyl)-[1-(4-methoxy-benzyl)-1,2,3,4-tetrahydro-quinolin-6-yl]-methanol(2.31 g).

¹H NMR (400 MHz, CDCl₃): δ 1.95-2.10 (m, 3H), 2.77 (t, J=6.4 Hz, 2H),3.33 (t, J=5.6 Hz, 2H), 3.78 (s, 3H), 4.39 (s, 2H), 5.96 (d, J=3.6 Hz,1H), 6.46 (d, J=8.0 Hz, 1H), 6.84 (d, J=7.6 Hz, 2H), 6.91-7.91 (m, 7H).MS (ES) m/z 474.1 (M+2).

Step II: To an ice cold solution of(5-bromo-2-chloro-phenyl)-[1-(4-methoxy-benzyl)-1,2,3,4-tetrahydro-quinolin-6-yl]-methanol(2.2 g, 4.7 mmol) in dichloromethane (50 mL) was added Et₃SiH (3.7 mL,23.3 mmol) followed by BF₃.OEt₂ (1.5 mL, 11.6 mmol). The reactionmixture was stirred at room temperature overnight. The reaction wasquenched by the addition of aq. NaHCO₃. The volatiles were evaporatedunder reduced pressure; the resulting mixture was extracted withdichloromethane (2×50 mL), washed with brine (10 mL), dried over sodiumsulfate, concentrated and. purified by silica gel column chromatographyto give6-(5-Bromo-2-chloro-benzyl)-1-(4-methoxy-benzyl)-1,2,3,4-tetrahydro-quinoline(1.48 g).

¹H NMR (400 MHz, CDCl₃): δ 1.96-2.02 (m, 2H), 2.77 (t, J=6.0 Hz, 2H),3.32 (t, J=5.6 Hz, 2H), 3.79 (s, 3H), 3.89 (s, 2H), 4.39 (s, 2H),6.47-7.29 (m, 10H). MS (ES) m/z 458.1 (M+2).

Step III: To a stirred solution of6-(5-bromo-2-chloro-benzyl)-1-(4-methoxy-benzyl)-1,2,3,4-tetrahydro-quinoline(700 mg, 1.5 mmol) in THF-toluene (15 mL of 1:2 mixture) was added 1.6 Msolution of n-BuLi in hexanes (1.0 mL, 1.5 mmol) at −78° C. The reactionmixture was stirred for 30 min., and then transferred to a stirredsolution of 2,3,4,6-tetrakis-O-(trimethylsilyl)-D-glucopyranone (715 mg,1.5 mmol) in toluene (10 mL) at −78° C. After stirring for 40 min., 0.6N methanesulfonic acid in methanol (30 mL) was added and stirred for 20h at room temperature. Reaction was quenched by the addition of aq.saturated NaHCO₃ (10 mL) and extracted with ethyl acetate (3×20 mL),dried over sodium sulphate, concentrated and purified by silica gelcolumn chromatography to furnish(2S,3R,4S,5S,6R)-2-{4-chloro-3-[1-(4-methoxy-benzyl)-1,2,3,4-tetrahydro-quinolin-6-ylmethyl]-phenyl}-6-hydroxymethyl-2-methoxy-tetrahydro-pyran-3,4,5-triol(330 mg).

MS (ES) m/z 570.2 (M+1).

Step IV: To a stirred solution of(2S,3R,4S,5S,6R)-2-{4-chloro-3-[1-(4-methoxy-benzyl)-1,2,3,4-tetrahydro-quinolin-6-ylmethyl]-phenyl}-6-hydroxymethyl-2-methoxy-tetrahydro-pyran-3,4,5-triol(325 mg, 0.6 mmol) in acetonitrile-dichloromethane mixture (1:1 mixture,14 mL) was added triethylsilane (0.4 mL, 2.2 mmol) and boron trifluoridediethyletharate complex (0.15 mL, 1.1 mmol) at −20° C. After stirringfor 4 h at 0° C., reaction was quenched with aq. saturated NaHCO₃solution (8 mL). The volatiles were evaporated under reduced pressure;the resulting mixture was extracted with ethyl acetate (3×20 mL). Theorganic layer was washed with brine (5 mL), dried over sodium sulphate,concentrated and purified by preparative HPLC to furnish(2S,3R,4R,5S,6R)-2-{4-chloro-3-[1-(4-methoxy-benzyl)-1,2,3,4-tetrahydro-quinolin-6-ylmethyl]-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol(160 mg).

¹H NMR (400 MHz, CD₃OD): δ 1.91-1.96 (m, J=5.6 Hz, 2H), 2.70 (t, J=6.4Hz, 2H), 3.25-3.44 (m, 6H), 3.67 (dd, J=12.0, 5.6 Hz, 1H), 3.74 (s, 3H),3.84-3.95 (m, 3H), 4.06 (d, J=9.6 Hz, 1H), 4.36 (s, 2H), 6.44 (d, J=9.2Hz, 1H), 6.74 (d, J=7.2 Hz, 2H), 6.83 (d, J=8.8 Hz, 2H), 7.15 (d, J=8.8Hz, 2H), 7.22-7.28 (m, 2H), 7.31 (d, J=8.0 Hz, 1H).

MS (ES) m/z 540.0 (M+1).

Example 15(2S,3R,4R,5S,6R)-2-[4-Chloro-3-(1,2,3,4-tetrahydro-quinolin-6-ylmethyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol

To a solution of(2S,3R,4R,5S,6R)-2-{4-chloro-3-[1-(4-methoxy-benzyl)-1,2,3,4-tetrahydro-quinolin-6-ylmethyl]-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol(135 mg, 0.25 mmol) in methanol (5 mL) was added 10% palladium oncharcoal (60 mg), 0.05 mL conc. HCl and stirred under hydrogen balloonpressure for 18 h. Reaction mixture was filtered through celite bed,washed with methanol and concentrated. The resulting residue waspurified by preparative HPLC to furnish(2S,3R,4R,5S,6R)-2-[4-Chloro-3-(1,2,3,4-tetrahydro-quinolin-6-ylmethyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol(74 mg).

¹H NMR (400 MHz, CD₃OD): δ 1.84-1.90 (m, 2H), 2.67 (t, J=6.8 Hz, 2H),3.17-3.20 (m, 2H), 3.25-3.46 (m, 4H), 3.65-3.69 (m, 1H), 3.84-3.96 (m,3H), 4.06 (d, J=9.2 Hz, 1H), 6.43 (d, J=8.0 Hz, 1H), 6.73-6.76 (m, 2H),7.23-7.28 (m, 2H), 7.32 (d, J=8.4 Hz, 1H).

MS (ES) m/z 420.0 (M+1).

Following examples were prepared using the procedures described forexamples 14 or

Example No. Structure/IUPAC name Spectral data 16

¹H NMR (400 MHz, CD₃OD): δ 1.84-1.89 (m, 2H), 2.68 (t, J = 6.4 Hz, 2H),3.18 (t, J = 5.2 Hz, 2H), 3.26-3.46 (m, 4H), 3.67 (dd, J = 12.0, 4.8,1H), 3.84-3.97 (m, 3H), 4.06 (d, J = 9.6 Hz, 1H), 6.34 (s, 1H), 6.40 (d,J = 7.6 Hz, 1H), 6.77 (d, J = 7.6 Hz, 1H), 7.24-7.33 (m, 3H). MS (ES)m/z 420.0 (M + 1). 17

¹H NMR (400 MHz, CD₃OD): δ 2.94 (t, J = 8.0 Hz, 2H), 3.26-3.45 (m, 6H),3.66-3.70 (m, 1H), 3.86 (d, J = 11.2 Hz, 1H), 3.95 (d, J = 15.2, 1H),4.01 (d, J = 15.2 Hz, 1H), 4.08 (d, J = 9.6 Hz, 1H), 6.62 (d, J = 8.0Hz, 1H), 6.85 (d, J = 7.6 Hz, 1H), 6.95 (s, 1H), 7.24-7.34 (m, 3H). MS(ES) m/z 406.0 (M + 1). 18

¹H NMR (400 MHz, CD₃OD): δ 2.82-2.89 (m, 4H), 3.25-3.47 (m, 4H),3.66-3.70 (m, 3H), 3.77 (s, 2H), 3.85-3.88 (m, 1H), 3.98-4.08 (m, 3H),6.84 (s, 1H), 6.98-7.40 (m, 10H). MS (ES) m/z 510.0 (M + 1). 19

¹H NMR (400 MHz, CD₃OD): δ 3.08 (t, J = 6.0 Hz, 2H), 3.27-3.49 (m, 6H),3.71 (dd, J = 11.6, 4.8 Hz, 1H), 3.88-3.91 (m, 1H), 4.06-4.15 (m, 3H),4.29 (s, 2H), 7.04 (s, 1H), 7.16 (s, 2H), 7.31-7.37 (m, 3H). MS (ES) m/z419.9 (M + 1). 20

¹H NMR (400 MHz, CD₃OD): δ 1.26 (s, 6H), 2.98 (s, 2H), 3.37-3.44 (m,4H), 3.65-3.70 (m, 1H), 3.85-3.98 (m, 3H), 4.08 (d, J = 9.48 Hz, 1H),6.43 (d, J = 8.16 Hz, 1H), 6.46 (s, 1H), 6.54 (d, J = 7.94 Hz, 1H), 7.25(d, J = 8.16 Hz, 1H), 7.30-7.34 (m, 2H). MS (ES) m/z 450.0 (M + 1) 21

¹H NMR (400 MHz, CD₃OD): δ 1.93-1.96 (m, 2H), 2.71 (t, J = 6.40 Hz, 2H),3.26-3.44 (m, 4H), 3.66-3.70 (m, 1H), 3.87 (d, J = 11.20 Hz, 1H), 3.90(d, J = 15.2 Hz, 1H), 3.99 (d, J = 14.8 Hz, 1H), 4.06-4.12 (m, 3H), 6.60(d, J = 8.16 Hz, 1H), 6.84-6.87 (m, 2H), 7.26 (dd, J = 8.16 Hz, 1.98 Hz1H), 7.30 (d, J = 1.98 Hz, 1H), 7.33 (d, J = 8.16 Hz, 1H). MS (ES) m/z420.9 (M + 1), 4437.9 (M + 18) 22

¹H NMR (400 MHz, CD₃OD): δ 3.17 (t, J = 8.56 Hz, 2H), 3.30-3.46 (m, 4H),3.66-3.70 (m, 1H), 3.85- 3.88 (m, 1H), 3.98 (d, J = 15.2 Hz, 1H), 4.02(d, J = 14.8 Hz, 1H), 4.07 (d, J = 9.2 Hz, 1H), 4.48 (t, J = 8.56 Hz,2H), 6.60 (d, J = 8.3 Hz, 1H), 6.91 (d, J = 8.1 Hz, 1H), 7.02 (s, 1H),7.26 (dd, J = 8.1 Hz, 2.0 Hz 1H), 7.31 (d, J = 1.7 Hz, 1H), 7.34 (d, J =8.1 Hz, 1H). MS (ES) m/z 424.0 (M + 18) 23

¹H NMR (400 MHz, CD₃OD): δ 1.84-1.90 (m, 2H), 2.18 (s, 3H), 2.67 (t, J =6.0 Hz, 2H), 3.16-3.19 (m, 2H), 3.35-3.48 (m, 4H), 3.68 (dd, J = 12.0,5.2, 1H), 3.78-3.88 (m, 3H), 4.06 (d, 8.8 Hz, 1H), 6.27 (d, J = 1.6 Hz,1H), 6.36 (dd, J = 7.6, 1.6 Hz, 1H), 6.76 (d, J = 7.6 Hz, 1H), 7.00 (d,J = 7.2 Hz, 1H), 7.15-7.18 (m, 2H). MS (ES) m/z 400.3 (M + 1). 24

¹H NMR (400 MHz, CD₃OD): δ 3.29-3.48 (m, 6H), 3.71 (dd, J = 12.0, 5.2Hz, 1H), 3.79-3.91 (m, 3H), 4.10 (d, J = 9.2, 1H), 4.17 (t, J = 4.4 Hz,2H), 6.46- 6.52 (m, 2H), 6.59 (d, J = 8.0 Hz, 1H), 7.01-7.31 (m, 3H). MS(ES) m/z 406.3 (M + 1). 25

¹H NMR (400 MHz, CD₃OD): δ 3.27-3.45 (m, 4H), 3.66-3.70 (dd, J = 12.0,5.6 Hz, 1H), 3.76-3.89 (m, 6H), 4.05 (d, J = 9.6, 1H), 4.18 (s, 4H),6.64-6.67 (m, 3H), 6.92 (d, J = 8.4 Hz, 1H), 7.17 (d, J = 2.0 Hz, 1H),7.25 (dd, J = 8.0, 2.0 Hz, 1H). MS (ES) m/z 436.0 (M + 18). 26

¹H NMR (400 MHz, CD₃OD): δ 1.84-1.88 (m, 2H), 2.67 (d, J = 6.4 Hz, 2H),3.17 (t, J = 6.4 Hz, 2H), 3.25-3.44 (m, 4H), 3.65 (dd, J = 12.0, 4.8,1H), 3.74-3.86 (m, 6H), 4.01 (d, J = 9.2 Hz, 1H), 6.41 (d, J = 8.0 Hz,1H), 6.73-6.75 (m, 2H) 6.89 (d, J = 8.8 Hz, 1H), 7.12 (d, J = 1.6 Hz,1H), 7.21 (dd, J = 8.4, 2.0 Hz, 1H). MS (ES) m/z 416.0 (M + 1). 27

¹H NMR (400 MHz, CD₃OD): δ 1.84-1.88 (m, 2H), 2.66 (d, J = 6.4 Hz, 2H),3.17 (t, J = 6.4 Hz, 2H), 3.25-3.43 (m, 4H), 3.65 (dd, J = 12.0, 5.2,1H), 3.72-3.86 (m, 6H), 4.01 (d, J = 9.2 Hz, 1H), 6.36-6.42 (m, 2H),6.73 (d, J = 7.6 Hz, 1H) 6.89 (d, J = 8.8 Hz, 1H), 7.14 (d, J = 2.0 Hz,1H), 7.21 (dd, J = 8.4, 2.0 Hz, 1H). MS (ES) m/z 416.1 (M + 1). 28

¹H NMR (400 MHz, CD₃OD): δ 3.26-3.47 (m, 6H), 3.66-3.70 (m, 1H),3.85-3.96 (m, 3H), 4.07 (d, J = 9.5 Hz, 1H), 4.15 (t, J = 4.4 Hz, 2H),6.40-6.45 (m, 2H), 6.56 (d, J = 8.0 Hz, 1H), 7.24-7.30 (m, 2H), 7.32 (d,J = 8.4 Hz, 1H),. MS (ES) m/z 421.9 (M + 1). 29

¹H NMR (400 MHz, CD₃OD): δ 0.80-0.83 (m, 2H), 0.96-0.99 (m, 2H), 1.82(t, J = 5.1 Hz, 2H), 3.27-3.45 (m, 4H), 3.66- 3.70 (m, 1H), 3.87 (d, J =11.7 Hz, 1H), 3.92 (d, J = 15.2 Hz, 1H), 3.97 (d, J = 15.2 Hz, 1H), 4.07(d, J = 9.2 Hz, 1H), 4.20 (t, J = 5.1 Hz, 2H), 6.55 (d, J = 2.2 Hz, 1H),6.61 (d, J = 8.3 Hz, 1H), 6.81 (dd, J = 8.3 Hz, J = 2.2 Hz, 1H),7.25-7.27 (m, 2H), 7.33 (d, J = 8.1 Hz, 1H). MS (ES) m/z 447.2 (M + 1).30

¹H NMR (400 MHz, CD₃OD): δ 1.38 (t, J = 6.8 Hz, 3H), 3.25-3.28 (m, 1H),3.36-3.47 (m, 2H), 3.56- 3.67 (m, 3H), 3.76 (s, 2H), 3.84 (d, J = 11.6Hz, 1H), 4.01-4.05 (m, 2H), 4.17 (s, 3H), 4.65 (d, J = 8.4 Hz, 1H), 6.62(d, J = 6.4 Hz, 2H), 6.69 (d, J = 8.8 Hz, 1H), 6.86 (d, J = 2.1 Hz, 1H),7.04 (d, J = 8.4 Hz, 1H), 7.24 (s, 1H). MS (ES) m/z 449.9 (M + 18). 31

¹H NMR (400 MHz, CD₃OD): δ 3.25-3.28 (m, 1H), 3.3-3.88 (m, 3H), 3.67-3.75 (m, 2H), 3.76 (d, J = 10.8 Hz, 1H), 3.79 (s, 3H), 3.80-3.88 (m,2H), 4.02 (d, J = 9.2 Hz, 1H), 4.13 (t, J = 4.4 Hz, 2H), 6.43 (dd, J =8.0 & 1.6 Hz, 2H), 6.46 (s, 1H), 6.53 (d, J = 8.0 Hz, 1H), 6.90 (d, J =4.8 Hz, 1H), 7.14 (d, J = 2.0 Hz, 1H), 7.22 (dd, J = 8.4 & 2.0 Hz, 1H).MS (ES) m/z 418.0 (M + 1). 32

¹H NMR (400 MHz, CD₃OD): δ 1.94-1.97 (m, 2H), 2.71 (t, J = 6.4 Hz, 2H),3.27-3.28 (m, 1H), 3.31-3.44 (m, 3H), 3.66- 3.70 (m, 1H), 3.75 (d, J =6.4 Hz, 1H), 3.81 (s, 3H), 3.83-3.89 (m, 3H), 4.04 (d, J = 9.2 Hz, 1H),4.11 (t, J = 5.2 Hz, 1H), 6.58 (d, J = 8.0 Hz, 1H), 6.85-6.89 (m, 2H),6.92 (d, J = 8.4 Hz, 1H), 7.16 (d, J =2.0 Hz, 1H), 7.25 (dd, J = 8.4 &2.4 Hz, 1H). MS (ES) m/z 434.1 (M + 18). 33

¹H NMR (400 MHz, CD₃OD): δ 1.91-1.97 (m, 2H), 2.71 (t, J = 6.8 Hz, 2H),3.20-3.28 (m, 1H), 3.35-3.44 (m, 3H), 3.66- 3.70 (m, 1H), 3.84-3.94 (m,3H), 4.09-4.11 (m, 3H), 6.60 (d, J = 8.0 Hz, 1H), 6.84 (d, J = 8.3 Hz,2H), 7.23 (dd, J = 8.4 & 1.2 Hz, 1H), 7.33 (d, J = 6.0 Hz, 1H), 7.36(dd, J = 2.0 & 8.4 Hz, 1H). MS (ES) m/z 471.0 (M + 1).

Examples 34-35

Step I: To a stirred solution of acetic acid(2R,3R,4R,5S,6S)-3,4,5-triacetoxy-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-tetrahydro-pyran-2-ylmethylester (13.00 g, 22.56 mmol) prepared using the procedures described inJ. Med. Chem. 2008, 51(5),1145-49, in 1,2-dichloroethane (130 mL) wasadded acetyl chloride at 0° C. Subsequently, AlCl₃ (9.03 g, 67.68 mmol)was added over 30 min at a rate to ensure that the temperature did notexceed 4° C. After 1 h, the reaction mixture was taken to roomtemperature and stirred at 50° C. overnight. The reaction was quenchedby pouring over ice and the resulting suspension was diluted with water(100 mL) and extracted with dichloromethane (100×2 mL). The organiclayer was washed with water (50 mL), brine (50 mL) and dried overanhydrous sodium sulfate. Solvent was removed under reduced pressure toget a crude product (12 g).

¹H NMR (400 MHz, CD₃OD): δ 1.70 (s, 3H), 1.97 (s, 3H), 2.0 (s, 6H), 2.61(s, 3H), 3.96-4.0 (m, 1H), 4.07-4.17 (m, 3H), 4.31 (dd, J=12.4 Hz, 4.9Hz, 1H), 4.54 (d, J=9.8 Hz, 1H), 5.03 (t, J=9.8 Hz, 1H), 5.16 (t, J=9.5Hz, 1H), 5.37 (t, J=9.5 Hz, 1H), 6.88 (d, J=8.5 Hz, 1H), 7.26 (dd, J=8.3Hz, 1.95 Hz, 1H), 7.32-7.39 (m, 2H), 7.40 (d, J=8.3 Hz, 1H), 7.68 (d,J=2.2 Hz, 1H).

MS (ES) m/z 590.9 (M+1)

Step II: To acetic acid(2R,3R,4R,5S,6S)-3,4,5-triacetoxy-6-[3-(3-acetyl-4-hydroxy-benzyl)-4-chloro-phenyl]-tetrahydro-pyran-2-ylmethylester(12.00 g, 20.32 mmol) was added N,N-dimethyl formamide dimethyl acetal(3.0 mL, 22.35 mmol). The reaction mixture was stirred at 90° C.overnight. The reaction was quenched by the addition of water (30 mL)and extracted with ethyl acetate (150 mL×3), solvent was removed underreduced pressure to get a crude product (8.12 g). The crude product wasused for next reaction without any purification.

MS (ES) m/z 477.9 (M+1)

Example 346-[2-chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yl)-benzyl]-chromen-4-one

Step III: To(E)-1-{5-[2-Chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yl)-benzyl]-2-hydroxy-phenyl}-3-dimethylamino-propenone(8.00 g, 16.77 mmol) in chloroform (80 mL) was added conc. HCl (3 mL).The reaction mixture was refluxed overnight. The reaction was quenchedby the addition of water (50 mL) and extracted with ethyl acetate (150mL×3), solvent was removed under reduced pressure to get a crude product(4.0 g).

¹H NMR (400 MHz, CD₃OD): δ 3.28-3.47 (m, 5H), 3.70 (dd, J=12.0 Hz, 7.5Hz, 1H), 3.90 (d, J=11.5 Hz, 1H), 4.14 (d, J=9.5 Hz, 1H), 4.26 (d, J=3.9Hz, 1H), 6.35 (d, J=5.8 Hz, 1H), 7.34-7.41 (m, 2H), 7.45 (d, J=2.0 Hz,1H), 7.53 (d, J=8.8 Hz, 1H), 7.65 (dd, J=8.8 Hz, 2.2 Hz, 1H), 7.93 (d,J=2.2 Hz, 1H), 8.16 (d, J=5.8 Hz, 1H).

MS (ES) m/z 432.8 (M+1)

Example 356-[2-Chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yl)-benzyl]-chroman-4-one

Step IV: To a stirred solution of6-[2-chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yl)-benzyl]-chromen-4-one(0.10 g, 0.2315 mmol) in ethyl acetate (2.5 mL) was added 10% Palladiumon C (20 mg, 20% w/w) followed by methanol (2.5 mL). After stirring for18 h under hydrogen atmosphere, the reaction mixture was filteredthrough celite and concentrated to furnish the crude product, which wasfurther purified by Preparative HPLC to yield the title compound (41 mg)

¹H NMR (400 MHz, CD₃OD): δ 2.78 (t, J=6.6 Hz, 2H), 3.27-3.49 (m, 4H),3.71 (dd, J=12.0 Hz, 7.5 Hz, 1H), 3.90 (d, J=11.5 Hz, 1H), 4.04-4.13 (m,3H), 4.51 (t, J=7.0 Hz, 2H), 6.92 (d, J=8.5 Hz, 1H), 7.30-7.41 (m, 4H),7.65 (d, J=2.2 Hz, 1H).

MS (ES) m/z 434.9 (M+1)

Example 36(2S,3R,4R,5S,6R)-2-[4-Chloro-3-(4-hydroxy-chroman-6-ylmethyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol

To a solution of6-[2-chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yl)-benzyl]-chroman-4-one(0.1 g, 0.23 mmol) in methanol (3 mL) was added sodium borohydride(0.017 g, 0.46 mmol). The reaction mixture was stirred for 2 h andquenched by the addition of water (10 mL) and extracted with ethylacetate (150 mL×3), solvent was removed under reduced pressure to getcrude(2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-hydroxy-chroman-6-ylmethyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triolwhich was further purified by preparative HPLC (Yield=30 mg).

¹H NMR (400 MHz, CD₃OD): δ 1.95-2.06 (m, 2H), 3.26-3.46 (m, 5H), 3.68(dd, J=11.9 Hz, 5.1 Hz, 1H), 3.87 (d, J=11.5 Hz, 1H), 3.97-4.02 (m, 1H),4.08 (d, J=9.2 Hz, 1H), 4.15-4.20 (m, 2H), 4.65 (t, J=4.4 Hz, 1H), 6.66(d, J=8.3 Hz, 1H), 7.00 (d, J=8.8 Hz, 1H), 7.15 (s, 1H), 7.23-7.32 (m,2H), 7.33 (d, J=8.3 Hz, 1H).

MS (ES) m/z 453.9 (M+18)

Example 37(2S,3R,4R,5S,6R)-2-[4-Chloro-3-(spiro[chromane-2,1′-cyclopentane]-6-ylmethyl)phenyl]-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol

Step I: To the acetic acid(2R,3R,4R,5S,6S)-3,4,5-triacetoxy-6-[3-(3-acetyl-4-hydroxy-benzyl)-4-chloro-phenyl]-tetrahydro-pyran-2-ylmethylester(0.1 g, 0.17 mmol) was added cyclopentanone (0.015 mL, 0.17 mmol)followed by pyrrolidine (0.056 mL, 0.34 mmol). The reaction mixture wassubjected to microwave irradiation for 4 min. Reaction mixture wasquenched with water (3 mL), extracted with ethyl acetate (5 mL×3), andsolvent was removed under reduced pressure to get a crude product (0.1g) which was used for next reaction as such.

Step II: To a stirred solution of the crude product obtained in step 1in THF:MeOH (3:2, 5 mL) was added lithium hydroxide (0.02 g, 0.52 mmol)in water (1 mL). The reaction mixture was stirred for 3 h at roomtemperature, diluted with water (3 mL), extracted with ethyl acetate (5mL×3), solvent was removed under reduced pressure to get a crudeproduct, which was purified by column chromatography to yield the titlecompound (20 mg).

¹H NMR (400 MHz, CD₃OD): δ 1.64-1.86 (m, 6H), 2.00-2.04 (m, 2H), 2.81(s, 2H), 3.26-3.47 (m, 4H), 3.69 (dd, J=11.7 Hz, 4.9 Hz, 1H), 3.87 (d,J=11.9 Hz, 1H), 4.02-4.12 (m, 3H), 6.85 (d, J=8.3 Hz, 1H), 7.29-7.39 (m,4H), 7.60 (d, J=2.0 Hz, 1H).

MS (ES) m/z 489.4 (M+1)

Example 38(2S,3R,4R,5S,6R)-2-[4-Chloro-3-(spiro[chromane-2,1′-cyclopentane]-6-ylmethyl)phenyl]-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol

To6-[2-chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yl)-benzyl]-2,2-spirocyclopentyl-chroman-4-one(0.125 g, 0.26 mmol) in acetonitrile/1,2-dichloroethane (1:1 mixture, 2mL) was added triethylsilane (0.15 mL, 1 mmol) followed byborontrifluoride diethyletherate (0.06 mL, 0.5 mmol) at 0° C. Thereaction mixture was stirred at room temperature for 18 h and thenheated to 60° C. for 2 h, quenched with saturated NaHCO₃ (5 mL)extracted with dichloromethane (10 mL×3), solvent was removed underreduced pressure to get the crude product which was further purified bypreparative HPLC to yield the title compound (Yield=5 mg).

¹H NMR (400 MHz, CD₃OD): δ 1.61-1.70 (m, 6H), 1.86-1.89 (m, 6H), 2.75(t, J=6.6 Hz, 2H), 3.27-3.46 (m, 2H), 3.68-3.71 (m, 1H), 3.88 (d, J=11.4Hz, 1H), 3.99 (q, J=15.1 Hz, 2H), 4.11 (d, J=9.3 Hz, 1H), 6.59 (d, J=8.8Hz, 1H), 6.88-6.90 (m, 2H), 7.28 (d, J=7.8 Hz, 1H), 7.33-7.36 (m, 2H).

MS (ES) m/z 475.0 (M+1)

Following example was prepared by using the analogous proceduresdescribed for example 38.

Example No. Structure/IUPAC name Spectral data 39

¹H NMR (400 MHz, CD₃OD): δ 1.85-1.95 (m, 2H), 2.25 (d, J = 14 Hz, 2H),2.82 (s, 2H), 3.25-3.47 (m, 9H), 3.69 (dd, J = 11.7 & 4.6 Hz, 1H), 3.87(d, J = 11.5. Hz, 1H), 4.03-4.12 (m, 2H), 7.03 (d, J = 8.5 Hz, 1H),7.29-7.47 (m, 3H), 7.45 (d, J = 8.5 Hz, 1H), 7.64 (s, 1H). MS (ES) m/z503.9 (M + 1)

Example 40-41

Step I: To a stirred solution of 5-bromo-2-methoxybenzaldehyde (5.0 g,23.25 mmol) in toluene (50 mL) was added ethylene glycol (2.6 mL, 46.5mmol) and p-toluenesulfonic acid monohydrate (0.45 g, 2.32 mmol) and thereaction mixture was azeotroped for 2 h, quenched with sat. NaHCO₃ (50mL). Reaction mixture was concentrated under reduced pressure, extractedwith ethyl acetate (2×100 mL), washed with water, brine, dried oversodium sulfate, concentrated and purified by silica gel columnchromatography to furnish 2-(5-bromo-2-methoxy-phenyl)-[1,3]dioxolane(3.75 g).

Step II: To a stirred solution of compound prepared in step I (3.50 g,13.51 mmol) in THF (20 mL) was added n-butyl lithium (8.5 mL, 13.51mmol) at −78° C. and stirred for 1 h. Ttetra-OBn-glucaranolactone (7.25g, 13.51 mmol) in toluene (20 mL) was cooled to −78° C. and Ithium saltprepared above was added to this at −78° C. and stirred for 1 h,quenched with sat. NH₄Cl soln. (10 mL) and extracted with ethyl acetate(2×70 mL). The ethyl acetate layer was washed with water, brine, driedover sodium sulphate, concentrated and purified by silica gel columnchromatography to furnish(3R,4S,5R,6R)-3,4,5-Tris-benzyloxy-6-benzyloxymethyl-2-(3-[1,3]dioxolan-2-yl-4-methoxy-phenyl)-tetrahydro-pyran-2-ol(4.8 g).

Step III: To a stirred solution of compound prepared in step II (4.80 g,6.68 mmol) in THF (20 mL) was added 6N HCl (10 mL) and stirred for 16 h.This reaction mixture was concentrated under reduced pressure, dilutedwith ethyl acetate (100 mL) washed with sat. NH₄Cl (20 mL), dried oversodium sulfate, concentrated and purified by silica gel columnchromatography to furnish2-Methoxy-5-((3R,4S,5R,6R)-3,4,5-tris-benzyloxy-6-benzyloxymethyl-2-hydroxy-tetrahydro-pyran-2-yl)-benzaldehyde(3.2 g).

Step IV: To a stirred solution of6-bromospiro[chromane-2,1′-cyclobutane] (0.563 g, 2.23 mmol) in THF (3mL) at −78° C. was added n-butyl lithium (1.45 mL, 2.23 mmol) andstirred for 1 h. Compound obtained in step III (0.3 g, 0.45 mmol) intoluene (3 mL) was cooled to −78° C. and Ithium salt prepared above wasadded to this at −78° C. This reaction mixture was stirred for 1 h,quenched with sat. NH₄Cl (10 mL) and extracted with ethyl acetate (2×20mL). The ethyl acetate layer was washed with water, brine, dried oversodium sulphate, concentrated and purified by silica gel columnchromatography to furnish[2-methoxy-5-[(3R,4S,5R,6R)-3,4,5-tribenzyloxy-6-(benzyloxymethyl)-2-hydroxytetrahydropyran-2-yl]phenyl]-spiro[chromane-2,1′-cyclobutane]-6-yl-methanone(0.250 g).

Example 406-(2-Methoxy-5-((2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6(benzyloxymethyl)tetrahydro-2H-pyran-2-yl)benzyl)spiro[chroman-2,1′-cyclobutane

Step V: To a stirred solution of compound obtained in step IV (0.250 g,0.29 mmol) in DCE (2 mL) and acetonitrile (2 mL) at −30° C. was addedtriethylsilane (0.28 g, 1.03 mmol) followed byborntrifluoride.diethyletherate (0.13 g, 1.76 mmol) and stirred at −30°C. for 5 h and then at 25° C. for 16 h. Reaction was quenched with sat.NaHCO₃ (20 mL), the volatiles were evaporated under reduced pressure;the resulting mixture was extracted with dichloromethane (2×20 mL),washed with brine (5 mL), dried over sodium sulfate, concentrated andpurified by silica gel column chromatography to furnish the titledcompound (Yield=0.21 g).

Example 41(2S,3R,4R,5S,6R)-2-[4-methoxy-3-(spiro[chromane-2,1′-cyclobutane]-6-ylmethyl)phenyl]-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol

Step VI: To a stirred solution of (0.21 g, 0.25 mmol) in ethyl acetate(5 mL) was added Palladium on C 10% w/w (50 mg) followed by a drop ofconc. HCl was added. The reaction was stirred for 18 h under hydrogenatmosphere. Reaction mixture was filtered through celite andconcentrated to furnish the crude titled compound which was purified bypreparative HPLC (22 mg).

Following examples were prepared by using the analogous proceduresdescribed for examples 40-41.

Example No. Structure/IUPAC name Spectral data 42

¹H NMR (400 MHz, DMSO- D6): δ 3.09-3.26 (m, 3H), 3.43-3.46 (m, 1H),3.66- 3.71 (m, 1H), 3.92-3.97 (m, 2H), 4.00 (d, J = 9.2 Hz, 1H),4.10-4.12 (m, 1H), 4.46 (t, J = 6.0 Hz, 1H), 4.52 (s, 2H), 4.86 (d, J =6.0 Hz, 1H), 4.97-4.97 (m, 2H), 6.76-6.80 (m, 3H), 7.24 (dd, J = 8.0 Hz,1.6 Hz, 1H), 7.34 (d, J = 1.6 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 10.64(s, 1H). MS (ES) m/z 436.0 (M + 1). 43

¹H NMR (400 MHz, CD₃OD): δ 3.30-3.44 (m, 5H), 3.67 (dd, 1H), 3.79 (s,3H), 3.80-3.86 (m, 2H), 4.04 (d, J = 9.0 Hz, 1H), 4.49 (s, 2H),6.73-6.90 (m, 3H), 6.91 (d, J = 8.0 Hz, 1H), 7.18 (s, 1H), 7.25 (dd, J =8.31, 1.7 Hz, 1H) MS (ES) m/z 432.1 (M + 1) 44

¹H NMR (400 MHz, DMSO- D6): δ 1.88 (t, J = 6.4 Hz, 2H), 1.99-2.05 (m,2H), 2.09-2.13 (m, 2H), 2.70 (t, J = 6.8 Hz, 2H), 3.11-3.27 (m, 5H),3.39-3.47 (m, 2H), 3.68-3.71 (m, 1H), 3.88- 3.97 (m, 2H), 3.99 (d, J =9.2 Hz, 1H), 4.46 (t, J = 5.6 Hz, 1H), 4.85 (d, J = 6.0 Hz, 1H),4.96-4.98 (m, 2H), 6.63 (d, J = 8.8 Hz, 1H), 6.86-6.88 (m, 2H), 7.23(dd, J = 8.4 Hz, 2.0 Hz, 1H), 7.32 (d, J = 2.0 Hz, 1H), 7.38 (d, J = 8.0Hz, 1H), MS (ES) m/z 461.0 (M + 1)

Example 45-46

Step I: To a stirred solution of acetic acid(2R,3R,4R,5S,6S)-3,4,5-triacetoxy-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-tetrahydro-pyran-2-ylmethylester (4.0 g, 6.93 mmol) prepared using the procedures described in J.Med. Chem. 2008, 51(5), 1145-49, in dichloromethane (40 mL) was added 1molar solution of BBr₃ (34.6 mL, 34.6 mmol) at −78° C. under nitrogenatmosphere. Reaction was stirred at −78° C. for 1.5 h and −30° C. for 1h. Reaction mixture was poured over ice and neutralized with sat. NaHCO₃(20 mL), extracted with dichloromethane, concentrated and purified bysilica gel column chromatography to furnish acetic acid(2R,3R,4R,5S,6S)-3,4,5-triacetoxy-6-[4-chloro-3-(4-hydroxy-benzyl)-phenyl]-tetrahydro-pyran-2-ylmethylester (2.9 g).

Step II: To a stirred solution of compound prepared in step I (2 g, 3.64mmol) in dichloroethane (20 mL) was added TBAB (117 mg, 0.364 mmol), 6%aqueous nitric acid (20 mmol) at 0-5° C. and stirred at room temperaturefor 4 h. Organic layer was separated, washed with water and brine andconcentrated to furnish crude acetic acid(2R,3R,4R,5S,6S)-3,4,5-triacetoxy-6-[4-chloro-3-(4-hydroxy-3-nitro-benzyl)-phenyl]-tetrahydro-pyran-2-ylmethylester which was further purified by column chromatography (1.5 g)

Step III: To a stirred solution of compound prepared in step II (0.70 g,1.178 mmol) in anhydrous acetonitrile (10 mL) was added anhydrous Cs₂CO₃(1.5 g, 4.71 mmol) and 2-bromo-2-methyl-propionic acid ethyl ester (0.6mL, 5.89 mmol). Reaction was heated to reflux under nitrogen atmospherefor 15 h. Additional amount of 2-bromo-2-methyl-propionic acid ethylester (0.6 mL, 5.89 mmol) was added at room temperature and heatingcontinued for 15 h. Reaction mixture was filtered, residue was washedwith anhydrous acetonitrile and concentrated to obtain crude product,which contains varying amounts of products resulting from partialhydrolyses of acetates. The crude product was reacetylated by usingacetic anhydride, pyridine and DMAP in dichloromethane. Reaction wasquenched with aq. ammonium chloride, extracted with ethyl acetate (2×20mL), washed with dil HCl, water, dried over sodium sulfate, concentratedand purified by column chromatography furnished2-{4-[2-Chloro-5-((2S,3S,4R,5R,6R)-3,4,5-triacetoxy-6-acetoxymethyl-tetrahydro-pyran-2-yl)-benzyl]-2-nitro-phenoxy}-2-methyl-propionicacid ethyl ester (515 mg).

Example 45[(2R,3R,4R,5S,6S)-3,4,5-triacetoxy-6-[4-chloro-3-[(2,2-dimethyl-3-oxo-4H-1,4-benzoxazin-6-yl)methyl]phenyl]tetrahydropyran-2-yl]methylacetate

Step IV: To a stirred solution of compound prepared in step III (515 mg,0.73 mmol) in glacial acetic acid (8 mL) was added iron powder (400 mg,7.1 mmol) and stirred at 60° C. overnight. Reaction mixture was cooledto room temperature, diluted with EtOAc (15 mL) and filtered throughcelite. Filtrate was concentrated and purified by column chromatographyto furnish[(2R,3R,4R,5S,6S)-3,4,5-triacetoxy-6-[4-chloro-3-[(2,2-dimethyl-3-oxo-4H-1,4-benzoxazin-6-yl)methyl]phenyl]tetrahydropyran-2-yl]methylacetate (365 mg)

Example 466-[2-Chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yl)-benzyl]-2,2-dimethyl-4H-benzo[1,4]oxazin-3-one

Step V: To a stirred solution of compound prepared in step IV (141 mg,0.22 mmol) in methanol (6 mL) was added NaOMe (70 mg, 1.29 mmol) andstirred at room temperature for 3 h. The solvent was evaporated and thecrude product was purified by silica gel column chromatography to obtainthe title compound (50 mg)

¹H NMR (400 MHz, CD₃OD): δ 1.42 (s, 6H), 3.27-2.49 (m, 4H), 3.63-3.73(m, 1H), 3.86-3.92 (m, 1H), 4.04 (d, J=5.2 Hz, 2H), 4.09-4.14 (m, 1H),6.70-6.74 (m, 1H), 6.81-6.85 (m, 2H), 7.28-7.33 (m, 1H), 7.35-7.40 (m,2H)

MS (ES) m/z 464.0 (M+1)

Following example was prepared by using the analogous proceduresdescribed for examples 45-46.

Example No. Structure/IUPAC name Spectral data 47

¹H NMR (400 MHz, DMSO- D6): δ 3.09-3.26 (m, 5H), 3.33-3.46 (m, 2H),3.66- 3.71 (m, 1H), 3.85-4.03 (m, 3H), 4.40-4.46 (m, 1H), 4.49 (s, 2H),4.82-4.97 (m, 2H), 6.69-6.75 (m, 2H), 6.83 (d, J = 8.4 Hz, 1H), 7.23(dd, J = 8 & 2 Hz, 1H), 7.30 (d, J = 1.6 Hz, 1H), 7.36 (d, J = 8.4 Hz,1H). MS (ES) m/z 436.0 (M + 1).

Example 48-49

Step I. To a stirred solution of ethyl-1-hydroxycyclopropane carboxylate(2.93 g, 20.5 mmol) in THF (50 mL) was added sodium hydride (60% inmineral oil, 981 mg, 24.5 mmol) under argon atmosphere. After 10 min,15-crown-5 (0.2 mL) followed by 4-bromo-2-nitro-fluorphenol (4.5 g, 20.5mmol) were added. The reaction mixture was stirred at room temperatureovernight then quenched by the addition of methanol (1.5 mL) and dilutedwith ethyl acetate. The mixture was washed with brine, and the organiclayer was dried over anhydrous sodium sulfate, concentrated and purifiedby silica gel column chromatography to give1-(4-bromo-2-nitro-phenoxy)-cyclopropanecarboxylic acid ethyl ester(3.51 g).

¹H NMR (400 MHz, CDCl₃): δ 1.20 (t, J=6.8 Hz, 3H), 1.95-1.42 (m, 2H),1.65-1.69 (m, 2H), 4.19 (q, J=6.8 Hz, 2H), 7.05 (d, J=8.8 Hz, 1H), 7.58(dd, J=8.8, 2.8 Hz, 1H), 7.96 (d, J=2.4 Hz, 1H).

MS (ES) m/z 329.9 (M+1).

Step II. To a stirred solution of1-(4-bromo-2-nitro-phenoxy)-cyclopropanecarboxylic acid ethyl ester (3.5g, 10.6 mmol) in glacial acetic acid (40 mL) was added iron powder (5.9g, 106.1 mmol) at room temperature and the reaction mixture was heatedat 60° C. for 3 h. The mixture was cooled to room temperature, dilutedwith ethyl acetate, and filtered through celite bed. The filtrate wasconcentrated, and the resulting residue was taken in ethyl acetate andwashed with water and saturated sodium bicarbonate solution, then theorganic layer was dried over sodium sulfate, concentrated and theresulting residue was purified by silica gel column chromatography tofurnish 6-bromospiro[4H-1,4-benzoxazine-2,1′-cyclopropane]-3-one (2.51g).

¹H NMR (400 MHz, DMSO-d₆): δ 1.14-1.25 (m, 4H), 6.82 (d, J=8.4 Hz, 1H),7.03-7.06 (m, 2H), 10.86 (s, 1H).

MS (ES) m/z 256.2 (M+1).

Step III. To a stirred solution of6-bromospiro[4H-1,4-benzoxazine-2,1′-cyclopropane]-3-one (2.6 g, 10.2mmol) in THF (20 mL) was added 1 M solution of borane-tetrahydrofurancomplex in THF (51.0 mL, 51.2 mmol). After refluxing for 6 h, thereaction mixture was cooled to room temperature and quenced by theaddition of methanol. Volatiles were evaporated under reduced pressure,and the resulting residue was taken up in ethyl actate and washed withsaturated aq. sodium bicarbonate solution, water, and brine. The organiclayer was dried over sodium sulfate, concentrated, and the resultingresidue was purified by silica gel column chromatography to furnish6-bromospiro[3,4-dihydro-1,4-benzoxazine-2,1′-cyclopropane] (2.3 g).

¹H NMR (400 MHz, CDCl₃): δ 0.68-0.71 (m, 2H), 1.02-1.06 (m, 2H), 3.31(s, 2H), 3.87 (bs, 1H), 6.57 (d, J=8.8 Hz, 1H), 6.72 (dd, J=8.4, 2.4 Hz,1H), 6.77 (d, J=2.4 Hz, 1H).

MS (ES) m/z 240.1 (M+1).

Step IV. To a stirred solution of6-bromospiro[3,4-dihydro-1,4-benzoxazine-2,1′-cyclopropane] (3.11 g,12.9 mmol) in DMF (20 mL) was added potassium carbonate (3.6 g, 26.0mmol) and benzyl bromide (1.61 mL, 13.6 mmol). The reaction mixture washeated at 60° C. for 6 h then cooled to room temperature and quenched bythe addition of water. The reaction mixture was extracted withethylacetate (2×50 mL) and the combined organic layers were washed withwater (20 mL) and brine (20 mL), then dried over sodium sulfate,filtered and concentrated. The crude product was purified by silica gelcolumn chromatography to furnish4-benzyl-6-bromo-spiro[3H-1,4-benzoxazine-2,1′-cyclopropane] (1.13 g).

¹H NMR (400 MHz, CDCl₃): δ 0.62-0.65 (m, 2H), 1.02-1.05 (m, 2H), 3.26(s, 2H), 4.44 (s, 2H), 6.59 (d, J=8.4 Hz, 1H), 6.69 (dd, J=8.4, 2.4 Hz,1H), 6.79 (d, J=2.0 Hz, 1H), 7.27-7.36 (m, 5H).

MS (ES) m/z 330.0 (M+1).

Step V. To a stirred solution of4-benzyl-6-bromo-spiro[3H-1,4-benzoxazine-2,1′-cyclopropane] (1.12 g,3.4 mmol) in THF (10 mL) was added 1.6 M solution of n-BuLi in hexanes(2.12 mL, 3.4 mmol) at −78° C. The reaction mixture was stirred for 30min, and then transferred to a stirred solution of5-bromo-2-chlorobenzaldehyde (745 mg, 3.4 mmol) in THF (10 mL) at −78°C. After stirring for 1 h, the reaction was quenched by the addition ofsaturated ammonium chloride solution and extracted with ethyl acetate.The ethyl acetate layer was washed with water, brine, dried over sodiumsulphate, and concentrated. The resulting residue was purified by silicagel column chromatography to furnish(4-benzylspiro[3H-1,4-benzoxazine-2,1′-cyclopropane]-6-yl)-(5-bromo-2-chloro-phenyl)methanol(790 mg).

MS (ES) m/z 470.0 (M+1).

Step VI. To an ice cold solution of(4-benzylspiro[3H-1,4-benzoxazine-2,1′-cyclopropane]-6-yl)-(5-bromo-2-chloro-phenyl)methanol(780 mg, 1.7 mmol) in trifluoroacetic acid (4 mL) was addedtriethylsilane (1.32 mL, 8.3 mmol) followed by triflic acid (0.15 mL,1.7 mmol). After heating the mixture for 15 min at 50° C., the reactionwas cooled to room temperature. Trifluoroacetic acid was evaporatedunder reduced pressure, and the resulting residue was taken in saturatedaq. sodium bicarbonate solution and extracted with ethyl acetate. Theorganic layer was washed with water, brine, dried over sodium sulfate,and concentrated. The resulting residue was purified by silica gelcolumn chromatography to furnish4-benzyl-6-[(5-bromo-2-chloro-phenyl)methyl]spiro[3H-1,4-benzoxazine-2,1′-cyclopropane](715 mg).

¹H NMR (400 MHz, CDCl₃): δ 0.64-0.67 (m, 2H), 1.04-1.07 (m, 2H), 3.28(s, 2H), 3.88 (s, 2H), 4.42 (s, 2H), 6.42 (d, J=8.0 Hz, 1H), 6.51 (s,1H), 6.68 (d, J=8.0 Hz, 1H), 7.17-7.35 (m, 8H).

MS (ES) m/z 448.0 (M+1).

Step VII. To a stirred solution of4-benzyl-6-[(5-bromo-2-chloro-phenyl)methyl]spiro[3H-1,4-benzoxazine-2,1′-cyclopropane](710 mg, 1.6 mmol) in THF-toluene (20 mL of 1:2 mixture) was added 1.6 Msolution of n-BuLi in hexanes (1.6 mL, 1.6 mmol) at −78° C. The reactionmixture was stirred for 30 min, and then transferred to a stirredsolution of 2,3,4,6-tetrakis-O-(trimethylsilyl)-D-glucopyranone (730 mg,1.6 mmol) in toluene (15 mL) at −78° C. After stirring for 40 min, 0.6 Nmethanesulfonic acid in methanol (7 mL) was added and stirred for 20 hat room temperature. The reaction was quenched by the addition ofsaturated aq. sodium bicarbonate solution (8 mL) then extracted withethyl acetate (3×10 mL). The organic layer was dried over sodiumsulphate and concentrated. The resulting residue was purified by silicagel column chromatography to furnish(3R,4S,5S,6R)-2-[3-[(4-benzylspiro[3H-1,4-benzoxazine-2,1′-cyclopropane]-6-yl)methyl]-4-chloro-phenyl]-6-(hydroxymethyl)-2-methoxy-tetrahydropyran-3,4,5-triol(350 mg).

¹H NMR (400 MHz, CD₃OD): δ 0.67-0.66 (m, 2H), 0.87-0.92 (m, 2H), 3.00(s, 3H), 306 (d, J=9.6 Hz, 1H), 3.29 (s, 2H), 3.38-3.43 (m, 1H),3.53-3.57 (m, 1H), 3.71-3.98 (m, 5H), 4.38 (ABq, J=16.0, 4.0 Hz, 2H),6.38 (dd, J=8.4, 2.0 Hz, 1H), 6.52 (d, J=8.0 Hz, 1H), 6.55 (d, J=1.6 Hz,1H), 7.20-7.31 (m, 6H), 7.41 (dd, J=8.8, 2.0 Hz, 1H), 7.50 (d, J=2.4 Hz,1H).

MS (ES) m/z 558.2 (M+1).

Example 48(2S,3R,4R,5S,6R)-2-[3-[(4-benzylspiro[3H-1,4-benzoxazine-2,1′-cyclopropane]-6-yl)methyl]-4-chloro-phenyl]-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol

Step VIII. To a stirred solution of(3R,4S,5S,6R)-2-[3-[(4-benzylspiro[3H-1,4-benzoxazine-2,1′-cyclopropane]-6-yl)methyl]-4-chloro-phenyl]-6-(hydroxymethyl)-2-methoxy-tetrahydropyran-3,4,5-triol(340 mg, 0.6 mmol) in acetonitrile-dichloromethane (6 mL, 1:1 mixture)was added triethylsilane (0.4 mL, 2.4 mmol) and boron trifluoridediethyletharate complex (0.15 mL, 1.2 mmol) at −5° C. After stirring for4 h at 0° C., the reaction was quenched with saturated aq. sodiumbicarbonate solution (5 mL). The volatiles were evaporated under reducedpressure, and the resulting mixture was extracted with ethyl acetate(3×10 mL). The ethyl acetate layers were combined and washed with brine(10 mL), dried over sodium sulphate, and concentrated. The resultingresidue was purified by silica gel column chromatography to furnish(2S,3R,4R,5S,6R)-2-[3-[(4-benzylspiro[3H-1,4-benzoxazine-2,1′-cyclopropane]-6-yl)methyl]-4-chloro-phenyl]-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol(300 mg).

MS (ES) m/z 538.0 (M+1).

Example 49(2S,3R,4R,5S,6R)-2-[4-Chloro-3-(spiro[3,4-dihydro-1,4-benzoxazine-2,1′-cyclopropane]-6-ylmethyl)phenyl]-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol

Step IX. To a solution of(2S,3R,4R,5S,6R)-2-[3-[(4-benzylspiro[3H-1,4-benzoxazine-2,1′-cyclopropane]-6-yl)methyl]-4-chloro-phenyl]-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol(300 mg) in methanol (3 mL), was added ethyl acetate (0.5 mL), 10%palladium on charcoal (40 mg), and 0.3 mL conc. HCl. The reactionmixture was stirred under hydrogen balloon pressure for 2 h thenfiltered through a celite bed which was washed with methanol, and theresulting filtrate was concentrated to a residue which was purified bypreparative HPLC to furnish(2S,3R,4R,5S,6R)-2-[4-chloro-3-(spiro[3,4-dihydro-1,4-benzoxazine-2,1′-cyclopropane]-6-ylmethyl)phenyl]-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol(56 mg).

¹H NMR (400 MHz, CD₃OD): δ 0.65-0.68 (m, 2H), 0.89-0.92 (m, 2H), 3.20(s, 2H), 3.28-3.46 (m, 4H), 3.68 (dd, J=12.0, 5.6 Hz, 1H), 3.85-3.99 (m,3H), 4.07 (d, J=9.6 Hz, 1H), 6.44 (dd, J=8.0, 2.0 Hz, 1H), 6.50-6.52 (m,2H), 7.25 (dd, J=8.0, 2.0 Hz, 1H), 7.31-7.34 (m, 2H).

MS (ES) m/z 448.0 (M+1).

Example 50-51

Step I. To a stirred solution of acetic acid(2R,3R,4R,5S,6S)-3,4,5-triacetoxy-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-tetrahydro-pyran-2-ylmethylester (3.0 g, 5.2 mmol, prepared using the procedures described in J.Med. Chem. 2008, 51(5),1145-49) in dichloromethane (30 mL) was addedboron tribromide solution (1.0 M in DCM, 26.0 mL, 26.0 mmol) at −78° C.After stirring at −15° C. for 1 h, the reaction mixture was poured ontoan ice-cold saturated aqueous sodium bicarbonate solution. The mixturewas extracted with dichloromethane (2×50 mL), and the combined organiclayers were washed with water (20 mL) and brine (20 mL), then dried oversodium sulfate and concentrated to a residue which was purified bysilica gel column chromatography to furnished(2R,3R,4R,5S,6S)-3,4,5-triacetoxy-6-[4-chloro-3-(4-hydroxy-benzyl)-phenyl]-tetrahydro-pyran-2-ylmethylester (2.1 g).

MS (ES) m/z 549.3 (M+1).

Step II. To a stirred solution of(2R,3R,4R,5S,6S)-3,4,5-triacetoxy-6-[4-chloro-3-(4-hydroxy-benzyl)-phenyl]-tetrahydro-pyran-2-ylmethylester (5.4 g) in ethylenedichloride (55 mL) was added 6% HNO₃ (22.2 mL)and tetra-butyl ammonium bromide (324 mg).

The reaction mixture was heated at 50° C. for 15 min. then cooled anddiluted with dichloromethane. The mixture was washed with water,saturated aqueous sodium bicarbonate solution, brine, and the organiclayer was dried over anhydrous sodium sulfate then concentrated. Theresulting residue was purified by silica gel column chromatography tofurnish acetic acid(2R,3R,4R,5S,6S)-3,4,5-triacetoxy-6-[4-chloro-3-(4-hydroxy-3-nitro-benzyl)-phenyl]-tetrahydro-pyran-2-ylmethylester (4.2 g)

MS (ES) m/z 593.8 (M+1).

Step III. To a stirred solution of acetic acid(2R,3R,4R,5S,6S)-3,4,5-triacetoxy-6-[4-chloro-3-(4-hydroxy-3-nitro-benzyl)-phenyl]-tetrahydro-pyran-2-ylmethylester (1.71 g, 2.9 mmol) in glacial acetic acid (15 mL) was added ironpowder (3.22 g, 57.7 mmol). After stirring at 60° C. for 15 min, thereaction mixture was filtered through a celite bed. The filtrate wasconcentrated under reduced pressure, and the resulting residue was takenup in ethyl acetate and the solution was washed with water, saturatedaqueous sodium bicarbonate solution, and brine. The organic layer wasdried over anhydrous sodium sulfate and concentrated to a residue whichwas purified by silica gel column chromatography to furnish acetic acid(2R,3R,4R,5S,6S)-3,4,5-triacetoxy-6-[3-(3-amino-4-hydroxy-benzyl)-4-chloro-phenyl]-tetrahydro-pyran-2-ylmethylester (1.3 g)

MS (ES) m/z 563.9 (M+1).

Example 50 Acetic acid(2R,3R,4R,5S,6S)-3,4,5-triacetoxy-6-[4-chloro-3-(2-cyano-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-phenyl]-tetrahydro-pyran-2-ylmethylester

Step IV. To a stirred solution of acetic acid(2R,3R,4R,5S,6S)-3,4,5-triacetoxy-6-[3-(3-amino-4-hydroxy-benzyl)-4-chloro-phenyl]-tetrahydro-pyran-2-ylmethylester (1.8 g, 3.2 mmol) in acetonitrile (15 mL) was added2-chloroacrylonitrile (0.35 mL, 4.5 mmol) and potassium carbonate (882mg, 6.4 mmol). After the reaction was refluxed overnight, the mixturewas filtered through a celite bed. The filtrate was concentrated andpurified by silica gel column chromatography to furnish acetic acid(2R,3R,4R,5S,6S)-3,4,5-triacetoxy-6-[4-chloro-3-(2-cyano-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-phenyl]-tetrahydro-pyran-2-ylmethylester (440 mg).

MS (ES) m/z 615.2 (M+1).

Example 516-[2-Chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yl)-benzyl]-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonitrile

Step V. To a stirred solution of acetic acid(2R,3R,4R,5S,6S)-3,4,5-triacetoxy-6-[4-chloro-3-(2-cyano-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-phenyl]-tetrahydro-pyran-2-ylmethylester (430 mg) in THF: Methanol:water (2:1:1 mixture, 4 mL) was addedlithium hydroxide (20 mg). After stirring at room temperature overnight,the reaction mixture was concentrated. The resulting residue was takenup in 50% methanol in ethyl acetate then filtered through celite bed.The filtrate was concentrated, and the residue was purified bypreparative HPLC to furnish6-[2-chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yl)-benzyl]-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonitrile(35 mg).

¹H NMR (400 MHz, CD₃OD): δ 3.26-3.50 (m, 6H), 3.68 (dd, J=12.0 Hz, 4.8Hz, 1H), 3.85-3.97 (m, 3H), 4.08 (d, J=9.2 Hz, 1H), 5.25 (t, J=2.8 Hz,1H), 6.48-6.51 (m, 2H), 6.68 (d, J=8.0 Hz, 1H), 7.26 (dd, J=8.4 Hz, 2.4Hz, 1H), 7.32-7.34 (m, 2H).

MS (ES) m/z 447.1 (M+1).

Examples 52-53

Example 526-[2-chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yl)-benzyl]-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylicacid methyl ester

Step I. To a stirred solution of acetic acid(2R,3R,4R,5S,6S)-3,4,5-triacetoxy-6-[4-chloro-3-(2-cyano-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-phenyl]-tetrahydro-pyran-2-ylmethylester (180 mg) in methanol (2 mL) was added sodium methoxide (20 mg).After stirring at room temperature overnight, the reaction mixture wasconcentrated to furnish6-[2-chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yl)-benzyl]-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylicacid methyl ester. The resulting crude material was taken for thefurther conversion (195 mg).

MS (ES) m/z 480.1 (M+1).

Example 536-[2-Chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yl)-benzyl]-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylicacid

Step II. To a stirred solution of6-[2-chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yl)-benzyl]-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylicacid methyl ester (190 mg) in THF: Methanol: water (1:1:1 mixture, 1.5mL) was added lithium hydroxide (17 mg). After stirring at roomtemperature overnight, the reaction mixture was concentrated, and theresulting residue was taken up in 50% methanol in ethyl acetate. Thesolution was filtered through a celite bed, and the filtrate wasconcentrated to a residue which was purified by preparative HPLC tofurnish6-[2-chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yl)-benzyl]-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylicacid (23 mg).

¹H NMR (400 MHz, CD₃OD): δ 3.19-3.44 (m, 5H), 3.56 (dd, J=11.6 Hz, 2.8Hz, 1H), 3.68 (dd, J=12.0 Hz, 5.2 Hz, 1H), 3.84-3.97 (m, 3H), 4.07 (d,J=9.2 Hz, 1H), 4.33 (dd, J=8.0, 2.4 Hz, 1H), 6.42-6.45 (m, 2H), 6.71 (d,J=8.0 Hz, 1H), 7.24 (dd, J=8.4 Hz, 2.4 Hz, 1H), 7.29-7.32 (m, 2H).

MS (ES) m/z 466.0 (M+1).

Examples 54-56

Step I. To a stirred solution of 2-bromo-5-iodobenzoic acid (1.0 g, 3.06mmol) in DCM (5 mL) was added DMF (0.2 mL) and oxalyl chloride (0.44 mL,4.59 mmol) at 0° C. After complete addition, the reaction mixture wasstirred at room temperature for 3 h. The volatiles were evaporated underreduced pressure, and the crude product was dissolved in DCM (4 mL) andadded to chroman (488 mg, 3.67 mmol) which had been cooled to 0° C. Tothis mixture was added aluminum chloride (488 mg, 3.67 mmol) inportions. After stirring for 4 h, the reaction was quenched by pouringit into crushed ice. This was extracted with dichloromethane (50 mL×2).The dichloromethane layers were combined and washed with water (20 mL),saturated aqueous sodium bicarbonate solution (20 mL×2), and brine (20mL), then dried over sodium sulfate, and concentrated. The crude productwas purified by column chromatography to furnish(2-bromo-5-iodo-phenyl)-chroman-6-yl-methanone (1.2 g).

Step II. To a stirred solution of(2-bromo-5-iodo-phenyl)-chroman-6-yl-methanone (2.0 g, 4.51 mmol) inacetonitrile: dichloromethane (2:1 mixture, 9 mL) was addedtriethylsilane (2.52 mL, 15.78 mmol) and boron trifluoride diethyletherate complex (1.11 mL, 9.02 mmol) at 0° C. After stirring overnightat room temperature, reaction was quenched by the addition of saturatedaqueous sodium bicarbonate solution. Volatiles were evaporated underreduced pressure. The aqueous layer was extracted with ethyl acetate(2×20 mL). Ethyl acetate layer was washed with water, brine, dried oversodium sulfate, concentrated and purified by silica gel columnchromatography to furnish 6-(2-bromo-5-iodo-benzyl)-chroman (1.5 g).

¹H NMR (400 MHz, CDCl₃): δ 2.03 (m, 2H), 2.77 (t, J=6.4 Hz, 2H), 3.93(s, 2H), 4.18 (t, J=5.2 Hz, 2H), 6.73 (d, J=8.4 Hz, 1H), 6.83 (s, 1H),6.89 (dd, J=8.4 Hz, 1.6 Hz, 1H), 7.28 (s, 1H), 7.39 (dd, J=8.4 Hz, 2.0Hz, 1H), 7.44 (d, J=2.0 Hz, 1H).

Step III. To a stirred solution of 6-(2-bromo-5-iodo-benzyl)-chroman(1.0 g, 2.33 mmol) in dry THF (6 mL) was added n-BuLi (1.6 M in hexane,1.45 mL, 2.33 mmol) at −78° C. After stirring for 45 min, the reactionmixture was transferred to a cooled solution of2,3,4,6-tetrakis-O-(benzyl)-D-glucopyranone (1.66 g, 2.56 mmol) in THF(6 mL) at −78° C. After stirring for 1 h, a solution of methane sulfonicacid (0.3 mL) in methanol (6 mL) was added, and the reaction was allowedto attain room temperature. After stirring overnight, the reaction wasquenched by the addition of a saturated sodium bicarbonate solution (10mL), and the resulting mixture was extracted with ethyl acetate (50mL×3). The organic layers were combined and dried over sodium sulfate,concentrated and purified by silica gel column chromatography to furnish6-[2-bromo-5-((3R,4S,5R,6R)-3,4,5-tris-benzyloxy-6-benzyloxymethyl-2-methoxy-tetrahydro-pyran-2-yl)-benzyl]-chroman(900 mg).

Example 546-[2-bromo-5-((3S,4R,5R,6R)-3,4,5-tris-benzyloxy-6-benzyloxymethyl-tetrahydro-pyran-2-yl)-benzyl]-chroman

Step IV. To a stirred solution of6-[2-bromo-5-((3R,4S,5R,6R)-3,4,5-tris-benzyloxy-6-benzyloxymethyl-2-methoxy-tetrahydro-pyran-2-yl)-benzyl]-chroman(900 mg, 1.05 mmol) in acetonitrile: dichloromethane (1:1 mixture, 6 mL)was added triethylsilane (0.34 mL, 2.1 mmol) and boron trifluoridediethyletharate complex (0.19 mL, 1.58 mmol), at 0° C. After stirringfor 2 h, the reaction was quenched with saturated aqueous sodiumbicarbonate solution. The volatiles were evaporated under reducedpressure; the resulting mixture was extracted with ethyl acetate (2×10mL). The organic layers were combined and dried over sodium sulfate thenconcentrated to a residue which was purified by silica gel columnchromatography to furnish6-[2-bromo-5-((3S,4R,5R,6R)-3,4,5-tris-benzyloxy-6-benzyloxymethyl-tetrahydro-pyran-2-yl)-benzyl]-chroman(600 mg).

Example 556-[2-cyclopropyl-5-((3S,4R,5R,6R)-3,4,5-tris-benzyloxy-6-benzyloxymethyl-tetrahydro-pyran-2-yl)-benzyl]-chroman

Step V. To a stirred solution of6-[2-bromo-5-((3S,4R,5R,6R)-3,4,5-tris-benzyloxy-6-benzyloxymethyl-tetrahydro-pyran-2-yl)-benzyl]-chroman(300 mg, 0.363 mmol) in toluene (1.6 mL) was addedtricyclohexylphosphine (10 mg), potassium phosphate (346 mg, 1.63 mmol),water (81 μl), cyclopropylboronic acid (93 mg, 1.09 mmol). The reactionmixture was degassed for 45 min then palladium (II) acetate (4 mg) wasadded. After heating overnight at 100° C., the reaction mixture wascooled to room temperature and was filtered through celite. The celitewas washed with an additional ethyl acetate (30 mL) and the organiclayer of the filtrate was separated and washed with water (20 mL)followed by brine (20 mL), then dried over sodium sulfate andconcentrated to give crude product which was further purified by columnchromatography to furnish6-[2-cyclopropyl-5-((3S,4R,5R,6R)-3,4,5-tris-benzyloxy-6-benzyloxymethyl-tetrahydro-pyran-2-yl)-benzyl]-chroman(250 mg).

Example 56(2S,3R,4R,5S,6R)-2-(3-Chroman-6-ylmethyl-4-cyclopropyl-phenyl)-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol

Step VI. To a stirred solution of6-[2-cyclopropyl-5-((3S,4R,5R,6R)-3,4,5-tris-benzyloxy-6-benzyloxymethyl-tetrahydro-pyran-2-yl)-benzyl]-chroman(650 mg) in THF (5 mL) was added 10% palladium charcoal activated (dry)(100 mg), methanol (5 mL), and conc. HCl (0.2 mL). The reaction mixturewas stirred under hydrogen atmosphere (bladder pressure) overnight thenfiltered through a celite bed. The filtrate was concentrated andpurified by preparative HPLC to furnish(2S,3R,4R,5S,6R)-2-(3-chroman-6-ylmethyl-4-cyclopropyl-phenyl)-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol(63 mg).

¹H NMR (400 MHz, CD₃OD): δ 0.52-0.56 (m, 2H), 0.81-0.89 (m, 2H),1.80-1.85 (m, 1H), 1.90-1.96 (m, 2H), 2.69 (t, J=6.0 Hz, 2H), 3.29-3.47(m, 3H), 3.67 (dd, J=12.0 Hz, 5.0 Hz, 1H), 3.87 (dd, J=12.0 Hz, 1.6 Hz,1H), 4.07 (d, J=8.8 Hz, 2H), 4.11-4.09 (m, 4H), 6.58 (d, J=8.0 Hz, 1H),6.80-6.84 (m, 2H), 6.96 (d, J=8.0 Hz, 1H), 7.10-7.22 (m, 2H).

MS (ES) m/z 444.1 (M+18).

Examples 57-58

Step I: To a stirred solution of 2-bromo-5-iodobenzoic acid (25.0 g,76.48 mmol) in dichloromethane (200 mL) was added oxalylchloride (10.3mL, 114.74 mmol) at 0° C. followed by DMF (0.9 mL). After completeaddition, the reaction mixture was stirred at room temperature for 3 h.Volatiles were evaporated under reduced pressure to furnish2-bromo-5-iodo-benzoyl chloride (26.4 g). The crude product was used forthe next step immediately.

Step II: To a stirred solution of 2-bromo-5-iodo-benzoyl chloride (26.4g, 76.56 mmol) in dichloromethane (250 mL) was added benzo(1,4)-dioxane(10.41 g, 76.26 mmol) at 0° C. To this reaction mixture, AlCl₃ (40.78 g,305.47 mmol) was added in portions. After stirring overnight at roomtemperature, the reaction mixture was poured into crushed ice. Theresulting mixture was extracted with dichloromethane (500 mL×2). Thedichloromethane layers were combined and washed with water (200 mL),saturated aqueous sodium bicarbonate solution (200 mL×2), and brine (200mL), then dried over sodium sulfate and concentrated. The solid productwas triturated with hexanes, and the triturated product was dried undervacuum to furnish(2-bromo-5-iodo-phenyl)-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-methanone(30 g).

¹H NMR (400 MHz, DMSO-D₆): δ 4.29-4.37 (m, 4H), 7.02 (d, J=8.4 Hz, 1H),7.16 (d, J 20=2.4 Hz, 1H), 7.18-7.19 (m, 1H), 7.53 (d, J=8.4 Hz, 1H),7.77-7.81 (m, 1H), 7.82 (d, J=2.0 Hz, 1H).

Step III: To a stirred solution of(2-bromo-5-iodo-phenyl)-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-methanone(30.0 g, 67.4 mmol) in trifluoroacetic acid (100 mL) was addedtriethylsilane (86.2 mL, 539.3 mmol) followed by triflic acid (6.0 mL,67.42 mmol) at room temperature. After stirring for 25 min at roomtemperature, volatiles were evaporated under reduced pressure. Theresulting residue was taken up in ethyl acetate and washed withsaturated aqueous sodium bicarbonate solution (200 mL×2), water (200mL), and brine (200 mL), then dried over sodium sulfate, concentratedand purified by silica gel column chromatography to furnish6-(2-bromo-5-iodo-benzyl)-2,3-dihydro-benzo[1,4]dioxine (26.5 g).

¹H NMR (400 MHz, DMSO-D₆): δ 3.90 (s, 4H), 4.2 (s, 2H), 6.65 (dd, J=8.4Hz, J=2.0 Hz, 1H), 6.68 (d, J=2.0 Hz, 1H), 6.77 (d, J=8.4 Hz, 1H), 7.39(d, J=8.4 Hz, 1H), 7.50 (dd, J=8.4 Hz, J=2.4 Hz 1H), 7.67 (d, J=2.8 Hz,1H).

Step IV: To a stirred solution of6-(2-bromo-5-iodo-benzyl)-2,3-dihydro-benzo[1,4]dioxine (26.5 g, 61.47mmol) in THF:toluene 2:1 (300 mL) was added 1.6 M solution of n-BuLi inhexanes (42.3 mL, 67.62 mmol) at −78° C. The reaction mixture wasstirred for 1 h, and then transferred to a stirred solution of2,3,4,6-tetrakis-O-(trimethylsilyl)-D-glucopyranone (28.69 g, 61.47mmol) in toluene (100 mL) at −78° C. After stirring for 1 h, 0.6 Nmethanesulfonic acid in methanol (265 mL) was added dropwise and stirredthe reaction mixture for 16 h at room temperature. Reaction was quenchedby the addition of aq. NaHCO₃ solution (˜75 mL) and extracted with ethylacetate (250 mL×3), dried over sodium sulfate, concentrated and purifiedby silica gel column chromatography to furnish(3R,4S,5S,6R)-2-[4-Bromo-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-6-hydroxymethyl-2-methoxy-tetrahydro-pyran-3,4,5-triol(28.4 g)

Example 57[(2R,3R,4R,5S,6S)-3,4,5-triacetoxy-6-[4-bromo-3-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)phenyl]tetrahydropyran-2-yl]methylacetate

Step V: To a stirred solution of(3R,4S,5S,6R)-2-[4-bromo-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-6-hydroxymethyl-2-methoxy-tetrahydro-pyran-3,4,5-triol(28.4 g, 57.1 mmol) in acetonitrile-dichloromethane 1:1 (250 mL) wasadded triethylsilane (36.5 mL, 228.4 mmol) and boron trifluoridediethyletharate complex (14.1 mL, 114.2 mmol) at 10° C. After stirringfor 4 h at 10° C., the reaction was quenched with saturated aqueoussodium bicarbonate (˜100 mL). The organic layer was separated, and theaqueous layer was extracted with ethyl acetate (3×150 mL). The organiclayers were combined and dried over sodium sulfate, concentrated tofurnish(3R,4R,5S,6R)-2-[4-bromo-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol(28.4 g). Crude product was used for next reaction without purification.

Example 58[(2R,3R,4R,5S,6S)-3,4,5-triacetoxy-6-[4-bromo-3-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)phenyl]tetrahydropyran-2-yl]methylacetate

Step V: To a stirred solution of(3R,4R,5S,6R)-2-[4-Bromo-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol(28.4 g, 60.81 mmol) in dichloromethane (300 mL) was added pyridine (40mL, 486.5 mmol), acetic anhydride (50 mL, 486.5 mmol) and DMAP (740 mg,6.08 mmol) at room temperature. After stirring for 2 h, volatiles wereevaporated under reduced pressure. The resulting residue was taken up inethyl acetate (500 ml) and washed with 1N HCl (200 mL×2) followed bybrine (200 ml), then dried over sodium sulfate and concentrated. Theresulting crude compound was dissolved in ethanol (320 mL) at 65° C. andallowed to cool to room temperature while stirring. Light yellow solidformed was filtered and washed with cold ethanol (150 mL) followed byhexane (200 mL) to get acetic acid(2R,3R,4R,5S)-3,4,5-triacetoxy-6-[4-bromo-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-tetrahydro-pyran-2-ylmethylester powder (22.5 g, purity 98%).

Examples 59-60

Example 59 Acetic acid(2R,3R,4R,5S)-3,4,5-triacetoxy-6-[4-cyclopropyl-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-tetrahydro-pyran-2-ylmethylester

Step I: To a stirred solution of acetic acid(2R,3R,4R,5S)-3,4,5-triacetoxy-6-[4-bromo-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-tetrahydro-pyran-2-ylmethylester (10.0 g, 15.74 mmol) in toluene (100 mL) was addedtricyclohexylphosphine (1.76 g, 6.29 mmol), a solution of potassiumphosphate tribasic (13.3 g, 62.9 mmol) in water (15 mL), andcyclopropylboronic acid (4.06 g, 47.2 mmol). The reaction mixture wasdegassed for 45 min then palladium (II) acetate (529 mg, 2.3 mmol) wasadded. The reaction mixture was stirred at 90° C. overnight then cooledto room temperature and filtered through celite, and the celite waswashed with ethyl acetate (200 mL). The organic layer of the filtratewas separated and washed with water (100 mL) followed by brine (100 mL),then dried over sodium sulfate and concentrated to give crude productwhich was further purified by column chromatography to furnish aceticacid(2R,3R,4R,5S)-3,4,5-triacetoxy-6-[4-cyclopropyl-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-tetrahydro-pyran-2-ylmethylester (7.25 g, purity 98%) and this was recrystallized by absoluteethanol to give white solid (5.25 g, purity>99%).

¹H NMR (400 MHz, CDCl₃): δ 0.57-0.62 (m, 2H), 0.84-0.86 (m, 2H), 1.76(s, 3H), 1.77-1.80 (m, 1H), 1.99 (s, 3H), 2.05 (s, 3H), 2.08 (s, 3H),3.78-3.82 (m, 1H), 3.99-4.10 (ABq, J=15.6 Hz, 2H), 4.14 (dd, J=12.4 Hz,2.4 Hz, 1H), 4.22 (s, 4H), 4.26 (d, J=12.4 Hz, 4.8 Hz, 1H), 4.33 (d,J=9.6 Hz, 1H), 5.14 (t, J=9.2 Hz, 1H), 5.22 (t, J=9.2 Hz, 1H), 5.30 (t,J=9.2 Hz, 1H), 6.57-6.59 (m, 2H), 6.76 (dd, J=7.2 Hz, 2.0 Hz, 1H), 6.98(d, J=8.4 Hz, 1H), 7.02 (d, J=1.6 Hz, 1H), 7.17 (dd, J=8.0 Hz, 1.6 Hz,1H).

MS (ES) m/z 597.3 (M+1).

Example 60(2S,3R,4R,5S,6R)-2-[4-Cyclopropyl-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol

Step II: To a stirred solution of acetic acid(2R,3R,4R,5S)-3,4,5-triacetoxy-6-[4-cyclopropyl-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-tetrahydro-pyran-2-ylmethylester (10.5 g, 17.61 mmol) in methanol:THF:water 3:2:1 (120 mL) wasadded lithium hydroxide (813 mg, 19.37 mmol). After stirring for 2 h atroom temperature, the volatiles were evaporated under reduced pressure.The resulting residue was taken up in ethyl acetate (150 mL) and washedwith brine (75 mL), brine containing 10 mL of 5% aqueous KHSO₄ (75 mL),and brine (20 mL) again, then dried over sodium sulfate and concentratedto furnish(2S,3R,4R,5S,6R)-2-[4-cyclopropyl-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol(7.25 g)

¹H NMR (400 MHz, CD₃OD): δ 0.53-0.56 (m, 2H), 0.81-0.86 (m, 2H),1.80-1.82 (m, 1H), 3.34-3.45 (m, 4H), 3.67 (dd, J=12.0, 5.2 Hz, 1H),3.86 (d, J=11.6 Hz, 1H), 3.99-4.09 (m, 3H), 4.17 (s, 4H), 6.58-6.62 (m,2H), 6.68 (d, J=8.0 Hz, 1H), 6.96 (d, J=7.6 Hz, 1H), 7.19 (m, 2H). MS(ES) m/z 446.2 (M+18).

Example 61-62

Example 61 Acetic acid(2R,3R,4R,5S)-3,4,5-triacetoxy-6-[3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-tetrahydro-pyran-2-ylmethylester

Step I: To a stirred solution of acetic acid(2R,3R,4R,5S)-3,4,5-triacetoxy-6-[4-bromo-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-tetrahydro-pyran-2-ylmethylester (10.0 g, 15.74 mmol) in toluene (200 mL) was addedtricyclohexylphosphine (1.76 g, 6.29 mmol), a solution of potassiumphosphate tribasic (13.3 g, 62.9 mmol) in water (15 mL), andethylboronic acid (3.4 g, 47.2 mmol). The reaction mixture was degassedfor 45 min then palladium (II) acetate (529 mg, 2.3 mmol) was added.After refluxing overnight, the reaction mixture was cooled to roomtemperature, and water was added. The resulting mixture was extractedwith ethyl acetate, (2×200 mL), washed with water and brine, then driedover sodium sulfate, concentrated and purified by column chromatographyto furnish acetic acid(2R,3R,4R,5S)-3,4,5-triacetoxy-6-[3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-tetrahydro-pyran-2-ylmethylester (5.4 g).

Example 62(2S,3R,4R,5S,6R)-2-[3-(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol

Step II: To a stirred solution of acetic acid(2R,3R,4R,5S)-3,4,5-triacetoxy-6-[3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-tetrahydro-pyran-2-ylmethylester (9.3 g, 15.9 mmol) in methanol:THF:water 3:2:1 (170 mL) was addedlithium hydroxide (764 mg, 19.1 mmol). After stirring for 2 h at roomtemperature, the volatiles were evaporated under reduced pressure. Theresulting residue was taken up in ethyl acetate (150 mL) and washed withbrine (75 mL), brine containing 5 mL of 5% aqueous KHSO₄ (75 mL), andbrine (20 mL) again, then dried over sodium sulfate and concentrated tofurnish(2S,3R,4R,5S,6R)-2-[4-Cyclopropyl-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol(6.5 g)

¹H NMR (400 MHz, CD₃OD): δ 1.07 (t, J=7.6 Hz, 3H), 2.57 (q, J=7.6 Hz,2H), 3.34-3.50 (m, 4H), 3.68 (dd, J=12.0, 5.6 Hz, 1H), 3.85-3.91 (m,3H), 4.08 (d, J=9.6 Hz, 1H), 4.17 (s, 4H), 6.53-6.58 (m, 2H), 6.68 (d,J=8.4 Hz, 1H), 7.15-7.25 (m, 3H).

MS (ES) m/z 434.2 (M+18).

Examples 63-65

Step I. To a stirred solution of1-(2,3-dihydro-benzo[1,4]oxazin-4-yl)-2,2,2-trifluoro-ethanone (9.2 g,39.77 mmol) in dichloromethane (70 mL) was added 5-iodo-2-bromobenzoylchloride (13.7 g, 39.77 mmol) in dichloromethane (30 mL) at 0° C.followed by addition of AlCl₃ (13.3 g, 99.41 mmol). After 3 h, thereaction mixture was brought to room temperature and stirred overnight.The reaction was quenched by pouring it over crushed ice and theresultanting mixture was extracted with dichloromethane (100×2 mL). Theorganic layers were combined and washed with aq. sodium bicarbonate (20mL) and water (20 mL) then concentrated to furnish6-(2-bromo-5-iodo-benzoyl)-4-(2,2,2-trifluoro-acetyl)-4H-benzo[1,4]oxazin-3-one(16.1 g).

MS (ES) m/z: 539.7 [M(⁷⁹Br)+1], 541.7 [M(⁸¹Br)+1]

Step II. To a stirred solution of6-(2-bromo-5-iodo-benzoyl)-4-(2,2,2-trifluoro-acetyl)-4H-benzo[1,4]oxazin-3-one(16.0 g, 29.252 mmol) in 1,2-dichloroethane/MeCN (1:2 mixture, 60 mL)was added triethylsilane (9.9 mL, 62.43 mmol) and borontrifluoridediethyletherate complex (4.9 mL, 38.51 mmol) simultaneously at −10° C.After stirring overnight at room temperature, the reaction was heated at50° C. for 3 h. The reaction was quenched by the addition of aq. sodiumbicarbonate (50 mL). Volatiles were evaporated under reduced pressure,and the resulting residue was extracted with ethyl acetate (2×100 mL).The organic layers were combined and washed with water and brine, thendried over sodium sulfate and concentrated to a residue which waspurified by silica gel column chromatography to furnish1-[6-(2-bromo-5-iodo-benzyl)-2,3-dihydro-benzo[1,4]oxazin-4-yl]-2,2,2-trifluoro-ethanone(12.1 g).

MS (ES) m/z 544.7 (M+18)

Step III. To a stirred solution of1-[6-(2-bromo-5-iodo-benzyl)-2,3-dihydro-benzo[1,4]oxazin-4-yl]-2,2,2-trifluoro-ethanone(12.0 g, 22.81 mmol) in methanol (100 mL) and THF (20 mL) was addedsodium borohydride (1.73 g, 45.62 mmol) portion wise and the reactionmixture was stirred at room temperature for 1 h. The excess of sodiumborohydride was quenched by adding 1N HCl. Methanol was evaporated andthe residue was partitioned between dichloromethane and water. Theorganic layer was washed with water, and brine, then concentrated tofurnish the crude product which was purified by silica gel columnchromatography to provide6-(2-bromo-5-iodo-benzyl)-3,4-dihydro-2H-benzo[1,4]oxazine (9.45 g).

MS (ES) m/z: 429.8 [M(⁷⁹Br)+1], 431.8 [M(⁸¹Br)+1]

Step IV. To a stirred solution of6-(2-bromo-5-iodo-benzyl)-3,4-dihydro-2H-benzo[1,4]oxazine (9.4 g, 21.86mmol) in DMF (50 mL) was added potassium carbonate (6.04 g, 43.71 mmol),benzyl bromide (3.2 mL, 26.23 mmol) and the mixture was heated to 50° C.overnight. The reaction mixture was cooled to room temperature, quenchedby the addition of water (100 mL), then extracted with ethyl acetate(3×50 mL). The organic layers were combined then washed with water (50mL), brine (50 mL), dried over sodium sulfate, and concentrated to aresidue which was purified by silica gel column chromatography tofurnish4-benzyl-6-(2-bromo-5-iodo-benzyl)-3,4-dihydro-2H-benzo[1,4]oxazine(10.5 g).

MS (ES) m/z: 519.8 [M(⁷⁹Br)+1], 521.8 [M(⁸¹Br)+1]

Step V. To a stirred solution of4-benzyl-6-(2-bromo-5-iodo-benzyl)-3,4-dihydro-2H-benzo[1,4]oxazine (2.0g, 3.85 mmol) in THF (20 mL) was added n-Butyl lithium (2.4 mL, 3.85mmol) at −78° C. and the mixture was stirred for 1 h. This wastransferred to a solution of 2,3,4,6-tetrakis-O-(benzyl)-D-glucopyranone(2.07 g, 3.85 mmol) in THF (18 mL) at −78° C. After stirring for 1 h,the reaction was quenched with Sat. ammonium chloride (20 mL), and theresulting mixture was extracted with ethyl acetate (2×20 mL), washedwith water and brine, then dried over sodium sulfate, concentrated andpurified by silica gel column chromatography to furnish(3R,4S,5R,6R)-2-[3-(4-benzyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-4-bromo-phenyl]-3,4,5-tris-benzyloxy-6-benzyloxymethyl-tetrahydro-pyran-2-ol(1.62 g).

MS (ES) m/z: 931.9 [M(⁷⁹Br)+1], 934.0 [M(⁸¹Br)+1]

Example 634-Benzyl-6-[2-bromo-5-((2S,3S,4R,5R,6R)-3,4,5-tris-benzyloxy-6-benzyloxymethyl-tetrahydro-pyran-2-yl)-benzyl]-3,4-dihydro-2H-benzo[1,4]oxazine

Step VI. To a stirred solution of(3R,4S,5R,6R)-2-[3-(4-benzyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-4-bromo-phenyl]-3,4,5-tris-benzyloxy-6-benzyloxymethyl-tetrahydro-pyran-2-ol(1.60 g, 1.72 mmol) in acetonitrile-dichloromethane mixture (3:1mixture, 7 mL) was added triethylsilane (0.82 mL, 5.15 mmol) followed byboron trifluoride diethyletharate complex (0.42 mL, 3.43 mmol) at −30°C. After stirring for 2 h at 0° C., the reaction was quenched with aq.sodium bicarbonate (4 mL). The volatiles were evaporated under reducedpressure, and the resulting mixture was extracted with dichloromethane(2×20 mL). The organic layers were combined and washed with brine (3mL), dried over sodium sulfate, then concentrated to a residue which waspurified by column chromatography to furnish4-benzyl-6-[2-bromo-5-((2S,3S,4R,5R,6R)-3,4,5-tris-benzyloxy-6-benzyloxymethyl-tetrahydro-pyran-2-yl)-benzyl]-3,4-dihydro-2H-benzo[1,4]oxazine(1.10 g).

MS (ES) m/z: 917.1 [M(⁷⁹Br)+1], 919.1 [M(⁸¹Br)+1]

Example 644-Benzyl-6-[2-cyclopropyl-5-((2S,3S,4R,5R,6R)-3,4,5-tris-benzyloxy-6-benzyloxymethyl-tetrahydro-pyran-2-yl)-benzyl]-3,4-dihydro-2H-benzo[1,4]oxazine

Step VII. To a stirred solution of4-benzyl-6-[2-bromo-5-((2S,3S,4R,5R,6R)-3,4,5-tris-benzyloxy-6-benzyloxymethyl-tetrahydro-pyran-2-yl)-benzyl]-3,4-dihydro-2H-benzo[1,4]oxazine(0.35 g, 0.38 mmol) in toluene: water (10:1 mixture, 10 mL) was addedcyclopropylboronic acid (49.2 mg, 0.5731 mmol) tricyclohexylphosphine(26.7 mg, 0.0955 mmol), and potassium phosphate (0.28 g, 1.34 mmol). Thereaction mixture was degassed for 45 min then palladium (II) acetate(8.5 mg, 0.03821 mmol) was added. After heating overnight at 100° C.,the reaction mixture was cooled to room temperature and water (20 mL)was added. The resulting mixture was extracted with ethyl acetate (2×25mL), washed with water and brine, then dried over sodium sulfate,concentrated and purified by column chromatography to furnish4-benzyl-6-[2-cyclopropyl-5-((2S,3S,4R,5R,6R)-3,4,5-tris-benzyloxy-6-benzyloxymethyl-tetrahydro-pyran-2-yl)-benzyl]-3,4-dihydro-2H-benzo[1,4]oxazine(317 mg). The product was taken up for the next step withoutcharacterization.

Example 65(2S,3R,4R,5S,6R)-2-[4-Cyclopropyl-3-(3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol

Step VIII. To a solution of4-benzyl-6-[2-cyclopropyl-5-((2S,3S,4R,5R,6R)-3,4,5-tris-benzyloxy-6-benzyloxymethyl-tetrahydro-pyran-2-yl)-benzyl]-3,4-dihydro-2H-benzo[1,4]oxazine(0.42 g, 0.4783 mmol) in THF (4.7 mL) was added 10% palladium oncharcoal (80 mg), 0.1 mL conc. HCl followed by methanol (4.7 mL) and themixture was stirred under hydrogen atmosphere for 18 h. The reactionmixture was filtered through a celite bed, washed with methanol andconcentrated. The resulting residue was purified by preparative HPLC tofurnish(2S,3R,4R,5S,6R)-2-[4-cyclopropyl-3-(3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol(34 mg).

¹H NMR (400 MHz, CD₃OD): δ 0.53-0.57 (m, 2H), 0.82-0.86 (m, 2H),1.81-1.88 (m, 1H), 3.27 (t, J=11.0 Hz, 2H), 3.43-3.47 (m, 3H), 3.68 (dd,J=12.0 Hz, 5.6 Hz, 1H), 3.86 (d, J=11.6 Hz, 1H), 3.99 (Abq, J=15.6 Hz,2H), 4.08 (d, J=9.2 Hz, 1H), 4.13 (t, J=11.0 Hz, 2H), 6.39-6.41 (m, 2H),6.54 (d, J=8.0 Hz, 1H), 6.95 (d, J=8.4 Hz, 1H), 7.17-7.21 (m, 2H).

MS (ES) m/z 428.1 (M+1).

Following example was prepared by using the procedures described forexamples 63-65.

Example No. Structure/IUPAC name Spectral data 66

¹H NMR (400 MHz, CD₃OD): δ 1.07 (t, J = 7.6 Hz, 3H), 2.58 (q, J = 7.6Hz, 2H), 3.26-3.48 (m, 6H), 3.66-3.70 (m, 1H), 3.80-3.89 (m, 3H), 4.07(d, J = 9.2 Hz, 1H), 4.13 (t, J = 4.4 Hz, 2H), 6.34-6.37 (m, 2H), 6.54(dd, J = 7.6, 0.8 Hz, 1H), 7.14 (d, J = 7.8 Hz, 1H), 7.18 (d, J = 1.6Hz, 1H), 7.22 (dd, J = 7.6, 1.6 Hz, 1H) MS (ES) m/z 416.4 (M + 1). 67

¹H NMR (400 MHz, CD₃OD): δ 2.36 (s, 3H), 3.26 (t, J = 4.4 Hz, 2H),3.37-3.45 (m, 5H), 3.65-3.80 (m, 3H), 3.88 (d, J = 11.4 Hz, 1H), 4.12(t, J = 4.4 Hz, 2H), 6.18 (dd, J = 8.1 Hz, 1.7 Hz, 1H), 6.25 (s, 1H),6.48 (d, J = 8.1 Hz, 1H), 7.07 (d, J = 8.0 Hz, 2H), 7.16 (d, J = 7.8 Hz,3H), 7.28-7.32 (m, 2H). MS (ES) m/z 4478.2 (M + 1).

Example 68-69

Step I: To a solution of 2-bromoisopropyl benzene (2.0 g, 10.0 mmole) indry THF (20 mL), nBuLi (1.6 M in hexane), (6.9 mL, 11.05 mmole) wasadded at −78° C. and the mixture was stirred at same temperature for onehour. DMF (0.9 g, 12.0 mmole) was added and the mixture was stirred at−78° C. for half an hour then allowed to stir at 0° C. for 15 min. Thereaction mixture was diluted with saturated aqueous ammonium chloride(10 mL) and extracted with EtOAc (3×30 mL). The organic layers werecombined and washed with brine, dried over sodium sulfate, andconcentrated to yield 2-isopropyl benzaldehyde (1.4 g).

Step II: A solution of 2-isopropyl benzaldehyde (1.5 g, 10.13 mmole) inDCM (10 mL) was added to a solution of AlCl₃ (2.6 g, 20.26 mmole) in DCM(10 mL) at 0° C. followed by addition of a dilute solution of Br₂ (0.67mL, 13.1 mmole in 20 mL DCM) to the reaction mixture. The solution wasstirred at 0° C. for 6 hours then stirred overnight at room temperature.The reaction mixture was basified using saturated aqueous sodiumbicarbonate and extracted with DCM (30×2 mL). The organic layers werecombined and the crude product was obtained by evaporation of thesolvent. The crude product was purified by column chromatography using1% EtOAc in Hexane to yield 5-bromo-2-isopropylbenzaldehyde (800 mg).

Step III: To a solution of4-Benzyl-6-bromo-3,4-dihydro-2H-benzo[1,4]oxazine (1.5 g, 4.93 mmol) inTHF (20 mL) was added 1.6 M n-butyl lithium in hexanes (3.0 mL, 74.93mmol) at −78° C. The reaction was stirred for 30 min. then transferredto a stirred solution of 5-bromo-2-isopropylbenzaldehyde (1.12 g, 4.93mmol) in THF (15 mL) at −78° C. After stirring for 30 min, the reactionwas quenched by the addition of saturated aqueous solution of ammoniumchloride. The resulting mixture was extracted with ethyl acetate (3×30mL), and the combined organic layers were washed with water (25 mL) andbrine (25 mL), then dried over sodium sulfate, concentrated and purifiedusing neutral alumina column chromatography to give(4-Benzyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-(5-bromo-2-isopropyl-phenyl)-methanol(1.3 g).

Step IV: To an ice cold solution of(4-Benzyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-(5-bromo-2-isopropyl-phenyl)-methanol(1.3 g, 2.87 mmol) in dichloromethane (25 mL) was added Et₃SiH (4.8 mL,5.70 mmol) followed by BF₃.OEt₂ (0.74 mL, 5.7 mmol). The reactionmixture was stirred at room temperature overnight then quenched by theaddition of aq. NaHCO₃. The reaction mixture was extracted with ethylacetate (3×30 mL), and the combined organic layers were washed withbrine (30 mL) and dried over sodium sulfate. Crude product obtainedafter evaporation of the solvent was purified by silica gel columnchromatography to furnish4-Benzyl-6-(5-bromo-2-isopropyl-benzyl)-3,4-dihydro-2H-benzo[1,4]oxazine(1.0 g).

Step V: To a stirred solution of4-Benzyl-6-(5-bromo-2-isopropyl-benzyl)-3,4-dihydro-2H-benzo[1,4]oxazine(1.0 g, 2.29 mmol) in THF-toluene (15 mL of 1:2 mixture) was added 1.6 Msolution of n-BuLi in hexanes (1.40 mL, 1.40 mmol) at −78° C. Thereaction mixture was stirred for 30 min. then transferred to a stirredsolution of 2,3,4,6-tetrakis-O-(trimethylsilyl)-D-glucopyranone (1.0 g,2.29 mmol) in toluene (10 mL) at −78° C. After stirring for 40 min., 0.6N methanesulfonic acid in methanol (10 mL) was added and the reactionwas stirred for 20 h at room temperature then quenched by the additionof aq. saturated NaHCO₃ (10 mL). The resulting mixture was extractedwith ethyl acetate (3×20 mL), and the organic layers were combined anddried over sodium sulphate, and concentrated to a residue which waspurified by silica gel column chromatography to furnish(3R,4S,5S,6R)-2-[3-(4-Benzyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-4-isopropyl-phenyl]-6-hydroxymethyl-2-methoxy-tetrahydro-pyran-3,4,5-triol(600 mg).

Example 68(2S,3R,4R,5S,6R)-2-[3-(4-Benzyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-4-isopropyl-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol

Step VI: To a stirred solution of(3R,4S,5S,6R)-2-[3-(4-Benzyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-4-isopropyl-phenyl]-6-hydroxymethyl-2-methoxy-etrahydro-pyran-3,4,5-triol(600 mg, 1.09 mmol) in acetonitrile-dichloroethane mixture (1:1 mixture,10 mL) was added triethylsilane (0.7 mL, 4.4 mmol) and boron trifluoridediethyletharate complex (0.27 mL, 2.18 mmol) at −20° C. After stirringfor 4 h at 0° C., the reaction was quenched with aq. saturated NaHCO₃solution (8 mL). The volatiles were evaporated under reduced pressure;the resulting mixture was extracted with ethyl acetate (3×20 mL). Theorganic layers were combined and washed with brine (5 mL), dried oversodium sulphate, concentrated to a residuer which was purified by columnchromatography to furnish(2S,3R,4R,5S,6R)-2-[3-(4-Benzyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-4-isopropyl-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol(520 mg).

Example 69(2S,3R,4R,5S,6R)-2-[3-(3,4-Dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-4-isopropyl-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol

Step VII: To a solution(2S,3R,4R,5S,6R)-2-[3-(4-benzyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-4-isopropyl-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol(520 mg, 1.0 mmol) in methanol (5 mL) was added 10% palladium oncharcoal (150 mg), 0.05 mL conc. HCl and the mixture was stirred underhydrogen balloon pressure for 18 h. The reaction mixture was filteredthrough a celite bed, and the celite was washed with methanol. Theresulting filtrate was concentrated to a residue which was purified bypreparative HPLC to furnish(2S,3R,4R,5S,6R)-2-[3-(3,4-Dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-4-isopropyl-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol(70 mg).

¹H NMR (400 MHz, CD₃OD): δ 1.06 (s, 3H), 1.08 (s, 3H), 3.10-3.180 (m,1H), 3.26-3.30 (m, 2H), 3.34-3.48 (m, 4H), 3.66-3.70 (m, 1H), 3.83-3.89(m, 3H), 4.07 (d, J=9.20 Hz, 1H), 4.11-4.13 (m, 2H), 6.32 (dd, J=2.4 Hz,J=8.4 Hz, 1H), 6.36 (d, J=1.6 Hz, 1H), 6.53 (d, J=8.4 Hz, 1H), 7.18 (s,1H), 7.24-7.28 (m, 2H). MS (ES) m/z 430.3 (M+1).

Examples 70-71

Step I: To a solution of 2-bromoisopropyl benzene (2.0 g, 10.0 mmole) indry THF (20 mL), nBuLi (1.6 M in hexanes) (6.9 mL, 11.05 mmole) wasadded at −78° C. and the mixture was stirred at same temperature for onehour. DMF (0.9 g, 12.0 mmole) was added and the mixture was stirred at−78° C. for an additional half an hour, then allowed to stir at 0° C.for 15 min. The reaction mixture was diluted with saturated aqueousammonium chloride (10 mL) and extracted with ethyl acetate (3×30 mL).The combined organic layers were washed with brine and dried over sodiumsulfate. The solvent was evaporated to yield 2-isopropyl benzaldehyde(1.4 g).

Step II: To a solution of trifluoroacetic acid (50 ml) and2-isopropylbenzaldehyde (2.0 g, 13.5 mmol) was added conc. sulphuricacid (98%) (10 ml) at room temperature, followed by N-bromosuccinamide(NBS, 3.6 g 20.2 mmol) in portions. After 2 hrs, the mixture was pouredinto ice water and extracted with dichloromethane (3×30 mL). The organiclayers were combined and neutralized with saturated aqueous sodiumbicarbonate, washed with brine (30 mL), dried over sodium sulfate andconcentrated. The resulting residue was purified by columnchromatography to furnish 5-bromo-2-isopropylbenzaldehyde (1.80 g).

¹H NMR (400 MHz, CDCl₃): δ 1.30 (d, J=6.8 Hz, 6H), 3.84-3.91 (m, 1H),7.33 (d, J=8.4 Hz, 1H), 7.65 (dd, J=2.0, J=8.4 Hz, 1H), 7.93 (d, J=2.0Hz, 1H), 10.3 (s, 1H).

Step I: To a stirred solution of 7-bromo-1,2,3,4-tetrahydroquinoline(7.0 g, 33.0 mmol) in DMF (50 mL) was added potassium carbonate (13.6 g,99.0 mmol), and benzyl bromide (4.33 mL, 36.3 mmol), and the mixture washeated to 60° C. for 12 h, then cooled to room temperature and quenchedby the addition of ice-cold water (150 mL). The resulting mixture wasextracted with ethyl acetate (3×50 mL), and the organic layers werecombined and washed with water (50 mL) and brine (50 mL), then driedover sodium sulfate, concentrated and purified by silica gel columnchromatography to furnish 1-benzyl-7-bromo-1,2,3,4-tetrahydro-quinoline(7.1 g).

Step II: To a solution of 1-benzyl-7-bromo-1,2,3,4-tetrahydro-quinoline(2.50 g, 8.27 mmol) in THF (20 mL) was added 1.6 M n-butyl lithium inhexanes (5.14 mL, 8.27 mmol) at −78° C. The mixture was stirred for 45min. then transferred to a stirred solution of5-bromo-2-isopropylbenzaldehyde (1.87 g, 8.27 mmol) in THF (15 mL) at−78° C. After stirring for 30 min, the reaction was quenched by theaddition of saturated aqueous solution of ammonium chloride, and theresulting mixture was extracted with ethyl acetate (3×30 mL). Theorganic layers were combined and washed with water (25 mL) and brine (25mL), then dried over sodium sulfate, concentrated and purified usingneutral alumina column chromatography to furnish(1-benzyl-1,2,3,4-tetrahydro-quinolin-7-yl)-(5-bromo-2-isopropyl-phenyl)-methanol(2.64 g).

¹H NMR (400 MHz, CDCl₃): δ 0.85 (d, J=7.2 Hz, 3H), 1.11 (d, J=6.8 Hz,3H), 1.97-2.03 (m, 2H), 2.78 (t, J=6.4 Hz, 2H), 2.92-2.99 (m, 1H), 3.40(t, J=5.6 Hz, 2H), 4.40 (s, 2H), 5.85 (d, J=3.2 Hz, 1H), 6.36 (s, 1H),6.47 (d, J=1.2 Hz, 1H), 6.91 (d, J=7.6 Hz, 1H), 7.04 (d, J=8.0 Hz, 1H),7.14-7.34 (m, 7H), 7.62 (d, J=2.0 Hz, 1H).

MS (ES) m/z 452 (M+2).

Step III: To a solution of(1-benzyl-1,2,3,4-tetrahydro-quinolin-7-yl)-(5-bromo-2-isopropyl-phenyl)-methanol(2.61 g, 5.79 mmol) in TFA (7.0 mL), Et₃SiH (4.63 mL, 28.95 mmol) wasadded followed by triflic acid (1.0 mL, 11.5 mmol) at room temperature.The reaction mixture was stirred at room temperature for 30 min. Thereaction was evaporated to dryness and neutralized by adding saturatedaqueous NaHCO₃ (15 mL). The resulting mixture was extraction withdichloromethane (3×30 mL). Crude product obtained after evaporationsolvent was purified by using neutral alumina column chromatography tofurnish1-benzyl-7-(5-bromo-2-isopropyl-benzyl)-1,2,3,4-tetrahydro-quinoline(1.80 g).

¹H NMR (400 MHz, CDCl₃): δ 1.05 (d, J=7.2 Hz, 6H), 1.96-2.02 (m, 2H),2.76 (t, J=6.0 Hz, 2H), 2.98-3.04 (m, 1H), 3.35 (t, J=5.6 Hz, 2H), 3.80(s, 2H), 4.37 (s, 2H), 6.19 (s, 1H), 6.27 (d, J=7.6 Hz, 1H), 6.85 (d,J=7.6 Hz, 1H), 7.07 (d, J=8.80 Hz, 1H), 7.14-7.29 (m, 7H).

MS (ES) m/z 436 (M+2).

Step IV: To a stirred solution of1-benzyl-7-(5-bromo-2-isopropyl-benzyl)-1,2,3,4-tetrahydro-quinoline(1.50 g, 3.45 mmol) in THF-toluene 1:2 (15 mL) was added 1.6 M solutionof n-BuLi in hexanes (2.16 mL, 3.45 mmol) at −78° C. The reactionmixture was stirred for 45 min., and then transferred to a stirredsolution of 2,3,4,6-tetrakis-O-(trimethylsilyl)-D-glucopyranone (1.60 g,3.45 mmol) in toluene (10 mL) at −78° C. After stirring for 45 min., 0.6N methanesulfonic acid in methanol (15 mL) was added and the mixture wasstirred for 20 h at room temperature. The reaction was quenched byaddition of aq. saturated NaHCO₃ (10 mL) and the resulting mixture wasextracted with ethyl acetate (3×20 mL). The organic layers were combinedand dried over sodium sulphate, concentrated and purified by silica gelcolumn chromatography to furnish(2S,3R,4S,5S,6R)-2-[3-(1-Benzyl-1,2,3,4-tetrahydro-quinolin-7-ylmethyl)-4-isopropyl-phenyl]-6-hydroxymethyl-2-methoxy-tetrahydro-pyran-3,4,5-triol(1.27 g).

Example 70(2S,3R,4R,5S,6R)-2-[3-(1-Benzyl-1,2,3,4-tetrahydro-quinolin-7-ylmethyl)-4-isopropyl-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol

Step V: To a stirred solution of(2S,3R,4S,5S,6R)-2-[3-(1-benzyl-1,2,3,4-tetrahydro-quinolin-7-ylmethyl)-4-isopropyl-phenyl]-6-hydroxymethyl-2-methoxy-tetrahydro-pyran-3,4,5-triol(1.20 g, 2.19 mmol) in acetonitrile-dichloroethane 1:1 (20 mL) was addedtriethylsilane (1.39 mL, 8.76 mmol) at room temperature, then thereaction mixture cooled to −50 to −60° C. and boron trifluoridediethyletharate complex (0.55 mL, 4.38 mmol) was added dropwise, and thereaction mixture was stirred at same temperature and allowed to stir atbelow −30° C. for 2 hours and at −20° C. for 1 hour and then below 0° C.for 1 hour. The reaction was quenched with aq. saturated NaHCO₃ solution(20 mL). The volatiles were evaporated under reduced pressure, and theresulting mixture was extracted with ethyl acetate (3×20 mL). Theorganic layers were combined and washed with brine (5 mL), dried oversodium sulphate, and concentrated to furnish(2S,3R,4R,5S,6R)-2-[3-(1-Benzyl-1,2,3,4-tetrahydro-quinolin-7-ylmethyl)-4-isopropyl-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol(1.0 g). Crude product was used for next step without purification.

Example 71(2R,3S,4R,5R,6S)-2-Hydroxymethyl-6-[4-isopropyl-3-(1,2,3,4-tetrahydro-quinolin-7-ylmethyl)-phenyl]-tetrahydro-pyran-3,4,5-triol

Step-VI: To a solution(2S,3R,4R,5S,6R)-2-[3-(1-benzyl-1,2,3,4-tetrahydro-quinolin-7-ylmethyl)-4-isopropyl-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol(1.0 g, 1.0 mmol) in methanol (20 mL) was added 10% dry palladium oncharcoal (200 mg) and conc. HCl (0.2 mL), and the mixture was stirredunder hydrogen balloon pressure for 18 h. The reaction mixture wasfiltered through a celite bed which was washed with methanol and thefiltrate was concentrated. The resulting residue was purified bypreparative HPLC to furnish(2R,3S,4R,5R,6S)-2-Hydroxymethyl-6-[4-isopropyl-3-(1,2,3,4-tetrahydro-quinolin-7-ylmethyl)-phenyl]-tetrahydro-pyran-3,4,5-triol(320 mg).

¹H NMR (400 MHz, CD₃OD): δ 1.07 (s, 3H), 1.08 (s, 3H), 1.84-1.88 (m,2H), 2.67 (t, J=6.4 Hz, 2H), 3.17 (t, J=5.6 Hz, 3H), 3.37-3.46 (m, 5H),3.65-3.70 (m, 1H), 3.83-3.88 (m, 2H), 4.08 (d, J=9.2 HZ, 1H), 6.26 (s,1H), 6.32 (d, J=8.0 Hz, 1H), 6.74 (d, J=7.60 Hz, 1H), 7.19 (s, 1H),7.22-7.26 (m, 2H).

MS (ES) m/z 428.1 (M+1).

Following example was prepared by using the procedures described forexamples 70-71.

Example No. Structure/IUPAC name Spectral data 72

¹H NMR (400 MHz, CD₃OD): δ 1.06 (s, 3H), 1.07 (s, 3H), 1.82- 1.88 (m,2H), 2.65 (t, J = 6.8 Hz, 2H), 3.12 (m, 1H), 3.16 (t, J = 10.20 Hz, 2H),3.38-3.46 (m, 4H), 3.66 (dd, J = 4.4 Hz, J = 12.0 Hz, 1H), 3.84-3.88 (m,3H), 4.08 (d, J = 9.2 HZ, 1H), 6.43 (d, J = 8.0 Hz, 1H), 6.63-6.70 (m,2H), 7.18 (s, 1H), 7.24-7.26 (m, 2H). MS (ES) m/z 428.1 (M + 1).

The below list of examples, but not limited to these, can also besynthesized following the general synthesis described herein above:

The inhibitory effect on the sodium-dependent glucose co-transporterSGLT, SGLT1 and SGLT2, of compounds of formula I may be demonstratedusing the following test procedures.

The ability of the substances to inhibit the SGLT-2 activity may bedemonstrated in a test set-up in which a CHO-K1 cell line (ATCC No. CCL6 1) or alternatively an HEK293 cell line (ATCC No. CRL-1573) is stablytransfected with an expression vector pZeoSV (Invitrogen, EMBL accessionnumber L36849) which contains the cDNA for the coding sequence of thehuman sodium glucose co-transporter 2 (Genbank Ace. No. NM_(—)003041)(CHO-hSGLT2 or HEK-hSGLT2). These cell lines transport 14 C-labelledalpha-methyl-glucopyranoside (14 C-AMG, Amersham) into the interior ofthe cell in sodium-dependent manner.

The SGLT-2 assay is carried out as follows: CHO-hSGLT2 cells arecultivated in Ham's F12 Medium (BioWhittaker) with 10% foetal calf serumand 250 μg/mL zeocin (Invitrogen), and HEK293-hSGLT2 cells arecultivated in DMEM medium with 10% foetal calf serum and 250 μg/mLzeocin (Invitrogen). The cells are detached from the culture flasks bywashing twice with PBS and subsequently treating with trypsin/EDTA.After the addition of cell culture medium the cells are centrifuged,resuspended in culture medium and counted in a Casy cell counter. Then40,000 cells per well are seeded into a white, 96-well plate coated withpoly-D-lysine and incubated overnight at 37° C., 5% CO2. The cells arewashed twice with 250 μl of assay buffer (Hanks Balanced Salt Solution,137 mM NaCl, 5.4 mM KCl, 2.8 mM CaCl2, 1.2 mM MgSO4 and 10 mM HEPES (pH7.4), 50 μg/mL of gentamycin). 250 μl of assay buffer and 5 μl of testcompound are then added to each well and the plate is incubated for afurther 15 minutes in the incubator. 5 μl of 10% DMSO are used as thenegative control. The reaction is started by adding 5 μl of 14 C-AMG(0.05 μCi) to each well. After 2 hours' incubation at 37° C., 5% CO2,the cells are washed again with 250 μl of PBS (200 C) and then lysed bythe addition of 25 μl of 0.1 N NaOH (5 min. at 37° C.). 200 μl ofMicroScint20 (Packard) are added to each well and incubation iscontinued for a further 20 min at 37° C. After this incubation theradioactivity of the 14 C-AMG absorbed is measured in a Topcount(Packard) using a 14 C scintillation program.

To determine the selectivity with respect to human SGLT1 an analogoustest is set up in which the cDNA for hSGLTI (Genbank Ace. No. NM000343)instead of hSGLT2 cDNA is expressed in CHO-K1 or HEK293 cells.

The compounds according to the invention may for example have EC50values below 1000 nM, particularly below 100 nM, most preferably below10 nM. The title compounds of the above Examples were evaluated in theabove described assay and the results of which are collated in Table 1.

TABLE 1 Example SGLT2 IC₅₀ SGLT1 IC₅₀ Number nM (n = 1-4) nM (n = 1-4) 12.7 655 2 11.1 2500 3 16 — 4 65 — 8 0.25 725 9 7.2 — 10 18 — 11 1.4 — 145.5 800 15 0.2 650 16 0.15 750 17 0.8 480 20 0.55 >3700 21 0.2 1100 220.4 — 24 1.3 31000 25 1.5 40 28 0.33 1000 29 84.5 7000 31 1.2 404 33 11157 35 9.5 1100 36 28 — 38 14.4 — 41 16.2 1620 42 0.35 105 43 3.9 59 4614 >3900 47 16.5 >3200 60 2.2 9 62 0.5 22 65 2.7 170 66 0.9 100 69 1.237 71 1.5 19

It can be seen that the compounds of the invention are useful asinhibitors of SGLT and therefore useful in the treatment of diseases andconditions mediated by SGLT such as the metabolic disorders disclosedherein.

Co-Crystal of the Compounds of the Invention

Method 1: 1:1 Co-Crystals of Compounds of the Invention with L-Proline

Proline co-crystals were prepared from Examples 8, 60, 62 and 71, by thefollowing method. The procedure given below pertains to the preparationof about 543 mg of the co-crystals for Examples 73-76.

Example 8, 60, 62 or 71 (about 4.28 mg) and L-proline (1.15 g) weretaken in 1:1 molar ratio in 10 ml of ethanol in a 25 ml round bottomflask and refluxed for one hour at 90° C. The ethanol was then removedunder vacuum (using rotatory vacuum evaporator) to yield a gummy paste.This gummy paste was stirred in 20 ml of hexane at room temperature for5 hrs (for Examples 60 and 62), overnight for Example 8 and 2 days forExample 71. The hexane was then decanted to yield a free flowing solid.Characterization data for co-crystals prepared by this method is shownin Examples 73-76.

Powder x-ray diffraction patterns for Examples 73-76 were measured usingthe following conditions:

Scanning Axis: Gonio Start Position (°2 Th.): 2.5167 End Position (°2Th.): 49.9707 Step Size (°2 Th.): 0.0330

Scan Step Time (sec): 10.1600

Scan Type: Continuous PSD Mode: Scanning PSD Length (°2 Th.): 2.12Offset (°2 Th.): 0.0000 Divergence Slit Type: Automatic IrradiatedLength (mm): 10.00 Specimen Length (mm): 10.00 Measurement Temperature(° C.): 25.00 Anode Material: Cu K-Alpha1 (Å): 1.54060 K-Alpha2 (Å):1.54443 K-Beta (Å): 1.39225 K-A2/K-A1 Ratio: 0.50000 Generator Settings:40 mA, 45 kV Goniometer Radius (mm): 240.00

Dist. Focus-Diverg. Slit (mm): 100.00

Incident Beam Monochromator: No Spinning: Yes Example 73 1:1 ProlineCo-crystal with(2S,3R,4R,5S,6R)-2-[4-Chloro-3-(3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol

(2S,3R,4R,5S,6R)-2-[4-Chloro-3-(3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol(Example 8) was completely amorphous initially but formed a crystallinecomplex with proline. This was confirmed by powder X-ray diffraction(PXRD) analysis. The stoichiometry of Example 8 and L-proline in theco-crystal prepared by the above method was found to be 1:1 by NMRspectroscopy & HPLC. Characterization data for co-crystals of Example 8and proline prepared by method 1 is shown in Table 1. Relativeintensities of the most prominent powder x-ray diffraction peaks forco-crystals of Example 8 and proline are shown in Table 1A.

TABLE 1 1:1 Co-crystal of Example 8 Proline Example 8 and proline IR(cm-1) 3337, 2875, 3053, 2983, 2777, 3585, 3208, 2914, 1613, 1594, 2369,1617, 1560, 1622,1591, 1513, 1513, 1478, 1449, 1405,1377, 1480,1457,1406, 1352, 1315, 1294,1256, 1169, 1369, 1317, 1291, 1289, 1211,1085, 1035, 983, 1214, 1127, 1075, 1083, 1039, 849 1034, 959, 922, 886,819 883, 836, 793 MP 74-126 205 decomposes 85-87 (° C.) PXRD (2 θ)amorphous 15.14, 18.04, 19.57, 5.7, 12.9, 16.6, 17.0, 24.80, 30.57,32.16, 19.3, 20.6, 22.3, 23.2, 39.79, 36.56, 37.65, 25.2, 25.7, 26.5,27.6 37.65 DSC Broad peak Sharp peak Three peaks were (° C.) observedobserved at 205 observed at from 63.78, 104.34 and 74-126 155.53

TABLE 1A Angle Relative Angle Relative (2-Theta) Intensity (%) (2-Theta)Intensity (%) 5.7 28.37 22.3 13.34 12.9 12.28 23.2 55.29 16.6 16.69 25.225.48 17.0 33.15 25.7 12.95 19.3 100.00 26.5 20.58 20.6 13.03 27.6 16.72

Example 74 1:1 Proline Co-crystal with(2S,3R,4R,5S,6R)-2-[4-Cyclopropyl-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol

(2S,3R,4R,5S,6R)-2-[4-Cyclopropyl-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol(Example 60) was completely amorphous initially but formed a crystallinecomplex with proline. This was confirmed by powder X-ray diffraction(PXRD) analysis. The stoichiometry of Example 60 and L-proline in theco-crystal prepared by method 1 was found to be 1:1 by NMR spectroscopy& HPLC. Characterization data for co-crystals of Example 60 and prolineprepared by the above method is shown in Table 2. Relative intensitiesof the most prominent powder x-ray diffraction peaks for co-crystals ofExample 60 and proline are shown in Table 2A.

TABLE 2 1:1 Co-crystal of Example 60 Proline Example 60 and proline IR3349, 2930, 2875, 3053, 2983, 2777, 3334, 2918, 2880, 1613, (cm-1) 1589,1506, 1458, 2369, 1617, 1560, 1589, 1505, 1455, 1427, 1429, 1360, 1284,1449, 1405, 1377, 1402, 1374, 1310, 1279, 1258, 1203, 1124, 1294, 1256,1169, 1262, 1199, 1165, 1124, 1086, 1068, 1020, 1085, 1035, 983, 1083,1068, 1041, 1019, 917, 886 849 954 MP 75-118 205 decomposes 148-158 (°C.) PXRD amorphous 15.14, 18.04, 19.57, 4.07, 15.41, 15.80, (2 θ) 24.80,30.57, 32.16, 16.16, 16.68, 17.04, 39.79, 36.56, 37.65, 17.59, 18.16,18.67, 37.65 19.53, 19.91, 20.36, 21.47, 21.88, 22.23, 23.84, 26.98,32.32 DSC Broad peak Sharp peak observed Sharp peak observed (° C.)observed from at 205 at 150.58 75-118

TABLE 2A Angle Relative Angle Relative (2-Theta) Intensity (%) (2-Theta)Intensity (%) 4.07 25.22 19.53 32.80 15.41 19.85 19.91 76.22 15.80 44.9020.36 52.35 16.16 87.61 21.47 34.08 16.68 100.00 21.88 48.13 17.04 36.5022.23 27.34 17.59 81.41 23.84 25.74 18.16 51.31 26.98 19.61 18.67 36.2732.32 15.11

Example 75 1:1 Proline Co-crystal with(2S,3R,4R,5S,6R)-2-[3-(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol

(2S,3R,4R,5S,6R)-2-[3-(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol(Example 62) was completely amorphous initially but formed a crystallinecomplex with proline. This was confirmed by powder X-ray diffraction(PXRD) analysis. The stoichiometry of Example 62 and L-proline in theco-crystal prepared by method 1 was found to be 1:1 by NMR spectroscopy& HPLC. Characterization data for co-crystals of Example 62 and prolineprepared by method 1 is shown in Table 3. Relative intensities of themost prominent powder x-ray diffraction peaks for co-crystals of Example62 and proline are shown in Table 3A.

TABLE 3 1:1 Co-crystal of Example 62 Proline Example 62 and proline IR3340, 2966, 2931, 3053, 2983, 2777, 3316, 3198, 2965, 2913, (cm-1) 2874,1589, 1506, 2369, 1617, 1560, 2873, 2679, 1605, 1505, 1456, 1429, 1358,1449, 1405, 1377, 1455, 1427, 1409, 1358, 1285, 1258, 1202, 1294, 1256,1169, 1311, 1286, 1257, 1201, 1124, 1085, 1068, 1085, 1035, 983, 1127,1085, 1069, 1018, 955, 917, 885, 833 849 1004, 918, 884 MP 76-123 205decomposes 146-151 (° C.) PXRD amorphous 15.14, 18.04, 19.57, 3.70,9.68, 11.07, (2 θ) 24.80, 30.57, 32.16, 14.26, 14.80, 15.40, 39.79,36.56, 37.65, 16.12, 16.59, 17.31, 37.65 17.98, 18.36, 18.88, 20.42,21.18, 22.50, 23.78, 24.56, 25.79, 27.46, 31.97, 32.46 DSC Broad peakSharp peak observed Two peaks were (° C.) observed at 205 observed at152.15 and from 75-118 163.81

TABLE 3A Angle Relative Angle Relative (2-Theta) Intensity (%) (2-Theta)Intensity (%) 3.70 15.78 18.36 25.18 9.68 10.68 18.88 36.33 11.07 21.2120.42 69.29 14.26 14.81 21.18 27.94 14.80 22.97 22.50 12.25 15.40 4.9823.78 33.08 16.12 8.45 24.56 6.92 16.59 18.78 25.79 21.69 17.31 100.027.46 8.90 17.60 20.35 31.97 7.65 17.98 47.20 32.46 5.98

Example 76 1:1 Proline Co-crystal with(2R,3S,4R,5R,6S)-2-Hydroxymethyl-6-[4-isopropyl-3-(1,2,3,4-tetrahydro-quinolin-7-ylmethyl)-phenyl]-tetrahydro-pyran-3,4,5-triol

(2R,3S,4R,5R,6S)-2-Hydroxymethyl-6-[4-isopropyl-3-(1,2,3,4-tetrahydro-quinolin-7-ylmethyl)-phenyl]-tetrahydro-pyran-3,4,5-triol(Example 71) was completely amorphous initially but formed a crystallinecomplex with proline. This was confirmed by powder X-ray diffraction(PXRD) analysis. The stoichiometry of Example 71 and L-proline in theco-crystal prepared by method 1 was found to be 1:1 by NMR spectroscopy& HPLC. Characterization data for co-crystals of Example 71 and prolineprepared by method 1 is shown in Table 4.

TABLE 4 1:1 Co-crystal of Example 71 and Example 71 Proline proline IR3318, 2959, 2928, 3053, 2983, 2777, 3311, 2959, 2926, (cm-1) 1659, 1614,1578, 2369, 1617, 1560, 1613, 1579, 1499, 1498, 1464, 1446, 1449, 1405,1377, 1406, 1361, 1314, 1361, 1313, 1180, 1294, 1256, 1169, 1170, 1084,1045, 1084, 1010, 886, 1085, 1035, 983, 1010, 833, 785 832, 786 849 PXRDAmorphous 15.14, 18.04, 19.57, 5.7, 8.8, 16.4, 19.1, (2 θ) 24.80, 30.57,32.16, 2.3, 23.6, 24.5 39.79, 36.56 37.65, 37.65 MP 76-120 205decomposes 145-148 (° C.) DSC Broad peak Sharp peak observed Two peaksobserved (° C.) observed at 76-120 at 205 at 156.29 and 158.38

Example 77 1:1 Proline Co-crystal with(2S,3R,4R,5S,6R)-2-[3-(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol

Method 2: 1:1 Co-Crystals of Example 62 with L-Proline

(2S,3R,4R,5S,6R)-2-[3-(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol(Example 62, 1500 mg, 3.6 mmol), L-proline (415 mg, 3.6 mmol) andethanol (23 mL) were added to a 50 mL 3-neck round bottom flask equippedwith nitrogen purging, magnetic stirring bar, thermometer pocket &calcium chloride guard tube and the mixture was stirred at 25-30° C. for30 min., then heat to reflux. A clear solution was observed which wasrefluxed for 30 min., then slowly cool to 25-30° C. causingprecipitation. Di-isopropyl ether (DIPE, 23 mL) was added whilemaintaining the mixture at 25-30° C. and stirring continuously foradditional one to two hours at the same temperature. The precipitate wascollected by filtration using vacuum (Nitrogen atmosphere), and thefilter cake was washed with ethanol-DIPE mixture (1:1 v/v, 10 ml)followed by DIPE (23 mL). The product was vacuum dried at 65-70° C. for5-6 hrs.

A melting point 136° C. (ΔH 53 J/g) was observed by differentialscanning calorimetry (DSC) and is shown in FIG. 1. A powder X-raydiffraction (PXRD) spectrum is shown in FIG. 2.

Example 78 2:1 Proline Co-crystal with(2S,3R,4R,5S,6R)-2-[3-(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol

Method 3: 1:2 Co-Crystals of Example 62 with L-Proline

(2S,3R,4R,5S,6R)-2-[3-(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol(Example 62, 1 kg) was added to 15 L of ethanol with agitation whilemaintaining the mixture at 20-25° C. The mixture was stirred for 10 minat 20-25° C., then L-proline (537 gm) was added while maintaining themixture at 20-25° C. The mixture was stirred at this temperature for 30min., then heated to reflux and refluxed for 30 min. The mixture wasslowly cooled to 25-30° C. then stirred for 1 hr. DIPE (15 L) was addedwhile maintaining the temperature at 25-30° C. and the mixture wasstirred at this temperature for 1 hr. The precipitated product wascollected by filtration and the product was washed with DIPE (5 L). Theproduct was air dried at 65-70° C. to yield 1.22 kg (79%) of a 1:2co-crystal of Example 62: L-proline. A melting point 176° C. (ΔH 85 J/g)was observed by differential scanning calorimetry (DSC) and is shown inFIG. 3. A powder X-ray diffraction (PXRD) spectrum is shown in FIG. 4.Relative intensities of the most prominent powder x-ray diffractionpeaks for the 1:2 co-crystals of Example 62 and proline are shown inTable 5.

TABLE 5 Angle Relative Angle Relative (2-Theta) Intensity (%) (2-Theta)Intensity (%) 6.1 28.1 17.8 100.0 9.1 53.9 18.9 39.0 12.8 22.7 20.9 39.515.2 34.4 28.4 20.4 16.5 28.3 — —

It will be understood that the invention has been described by way ofexample only and modifications may be made whilst remaining within thescope and spirit of the invention.

We claim:
 1. A crystalline form of L-proline co-crystal of(2S,3R,4R,5S,6R)-2-[4-Chloro-3-(3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol.2. The crystal according to claim 1, wherein the molar ratio ofL-proline to(2S,3R,4R,5S,6R)-2-[4-Chloro-3-(3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triolis about 1:1.
 3. The crystalline form according to claim 1, wherein thecrystalline form has a differential scanning calorimetry endotherm atabout 64° C., about 104° C. and/or about 157° C.
 4. A crystalline formof L-proline co-crystal of(2S,3R,4R,5S,6R)-2-[4-Cyclopropyl-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol.5. The crystal according to claim 4, wherein the molar ratio ofL-proline to(2S,3R,4R,5S,6R)-2-[4-Cyclopropyl-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triolis about 1:1.
 6. The crystalline form according to claim 4, wherein thecrystalline form has a differential scanning calorimetry endotherm atabout 151° C.
 7. A crystalline form of L-proline co-crystal of(2S,3R,4R,5S,6R)-2-[3-(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol.8. The crystal according to claim 7, wherein the molar ratio ofL-proline to(2S,3R,4R,5S,6R)-2-[3-(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triolis about 1:1.
 9. The crystalline form according to claim 7, wherein thecrystalline form has a differential scanning calorimetry endotherm atabout 136° C.
 10. The crystal according to claim 7, wherein the molarratio of L-proline to(2S,3R,4R,5S,6R)-2-[3-(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triolis about 2:1.
 11. The crystal according to claim 10, wherein thecrystalline form has a differential scanning calorimetry endotherm atabout 176° C.
 12. The crystalline form according to claim 10 having apowder X-ray diffraction pattern which is substantially the same as thepowder X-ray diffraction pattern shown in FIG. 4.